Sulphonamides derived from diarylmethanes, the processes for preparing them and pharmaceutical compositions containing them

ABSTRACT

The invention relates to new compounds corresponding to formula I: ##STR1## in which: W represents C=O, CH 2  or CHOH, 
     Z represents ##STR2## R 1  and R 2  represent especially Cl or F, R, R&#39; and R&#34; represent especially H, 
     X represents especially CH 2 , 
     Y represents especially COOH, 
     u and v are two integers ranging from 0 to 10, 
     p and q take the value 0 or 1, 
     n and m are two integers ranging 0 to 10 and 
     t is 0 or 1 
     the total number of carbon atoms in the chain ##STR3##  ranging from 2 to 20, and to their physiologically acceptable salts obtained with organic or inorganic acids. 
     These compounds are useful for preparing medicinal products which have, especially, anti-inflammatory properties.

The invention relates to new compounds, sulphonamides derived fromdiarylmethanes, in particular benzophenones, and from their isosteres,and also to their corresponding salts.

The invention also relates to a process for preparing these compounds.

The invention also relates to new medicinal products containing, by wayof active principle, these new compounds, and also their salts withphysiologically acceptable organic or inorganic acids or bases.

By medicinal products there is denoted any pharmaceutical compositioncontaining at least one of the chemical compounds defined below, incombination with a pharmaceutically acceptable vehicle.

Il will be called that the anti-inflammatories which are known and usedat present act:

either by inhibiting the biosynthesis of arachidonic acid at thephospholipase A₂ level; these are the corticoid anti-inflammatories(cortisones and derivatives), the use of which is limited by their sideeffects;

or by inhibiting the biosynthesis of prostaglandins at thecyclooxygenase level (both the thromboxane synthetase pathway and alsothe prostacyclin in synthetase pathway); these are the non-steroidanti-inflammatories.

Among non-steroid anti-inflammatories, there may be mentioned salicylderivatives such as aspirin, pyrazole derivatives such asphenylbutazone, arylalkanoic acids such as profens, and indolederivatives such as indomethacin.

As regards the non-steroid anti-inflammatories, these act in thebiosynthesis of prostaglandins by blocking cyclooxygenase, therebyblocking the formation of thromboxanes and prostacyclins; in particular,they can give rise to haemorrhagic accidents when they are combined withanticoagulant treatments.

The non-steroid anti-inflammatories can cause other adverse sideeffects, in particular gastralgia, nausea or vomiting, and for thisreason they cannot be used in the case of gastric or duodenal ulcer.

In fact, in the phenomena of inflammation, another class of mediators,the leukotrienes, which are metabolites of arachidonic acid, areinvolved.

The leukotrienes are powerful mediators which are involved in manyinflammatory, cardiovascular, allergic, cutaneous or asthmaticconditions.

The subject of the invention is to propose new compounds which arecapable of participating in the preparation of medicinal productspossessing, in particular, anti-inflammatory properties.

An advantageous aspect of the invention is to propose new compoundswhich do not inhibit cyclooxygenase and which are involved only at asubsequent stage in the biosynthesis of prostaglandins, endowing themwith a more specific action.

One of the aspects of the invention is to propose new compounds whichparticipate in the preparation of medicinal products capable of treatinginflammatory phenomena in particular, without affecting the biosynthesisof all prostaglandins.

In effect, they have little or no action on prostacyclin synthetase anddo not particularly inhibit the biosynthesis of prostacyclin in (PGI₂),which is vasodilatory and inhibits platelet aggregation.

In contrast, and advantageously, they are inhibitors or thromboxanesynthetase, an enzyme which is involved in the biosynthesis ofthromboxanes. It is known that thromboxane B₂, in particular, isinvolved in the phenomena of vasoconstriction of vessels and of plateletaggregation.

The products of the invention hence have a more specific activity at theplatelet level and are devoid of gastric side effects.

An advantageous aspect of the invention is to propose new compoundswhich have an effect on the biosynthesis of leukotrienes, especiallyinhibiting 5-lipoxygenase.

One of the aspects of the invention is to propose new compounds whichinhibit the biosynthesis of leukotrienes, more especially theleukotrienes B₄ (LTB₄) which are involved in the inflammatory processesand are produced by the polymorphonuclear luekocytes, and also theleukotrienes C₄ (LTC₄) involved in allergic reactions, in particularasthma, and certain types of allergic diseases.

Another aspect of the invention is to propose new compounds whichparticipate in the preparation of medicinal products capable of treatingthe pathological conditions in which leukotrienes, in particular LTB₄and LTC₄, are involved, such as allergic conditions, in particularcutaneous and asthmatic conditions, or inflammatory states.

They can even be administered in the case of renal insufficiency,because they have no inhibitory effect on the vasodilator renalprostaglandins such as PGE₂ and PGF₂ alpha.

These new compounds can also be used for the preparation of medicaments,liable to treat cardiovascular disorders in which the thromboxanesynthetases are implied, for instance prevention of thromboticaccidents.

In particular, the invention proposes new compounds which participate inthe formation of medicinal products having effective anti-inflammatoryproperties and having an improved therapeutic index.

One of the aspects of the invention is to provide a new family ofanti-inflammatory medicinal products which can inhibit the biosynthesisof leukotrienes, and have a selective action on thromboxane synthetase.

The invention relates to new sulphonamides derived from diarylmethanesand their isosteres corresponding to formula I: ##STR4## in which: Wrepresents C=O, CH₂ or CHOH,

Z represents; ##STR5## R₁ represents Cl, F, Br, NO₂, NH₂, CF₃, an alkylradical containing 1 to 4 carbon atoms, especially methyl or ethyl, analkoxy radical containing 1 to 4 carbon atoms, acetamido or benzamido,

R₂ represents Cl, F, Br, NO₂, NH₂, CF₃, an alkyl radical containing 1 to4 carbon atoms, especially methyl or ethyl, an lakoxy radical containing1 to 4 carbon atoms, acetamido or benzamido,

R represents H, an alkyl radical containing 1 to 6 carbon atoms or abenzyl radical,

R' and R" represent H or an alkyl radical containing 1 to 4 carbonatoms,

X represents (CH₂)_(r), r taking the value 0 or 1, or --CH═CH, ##STR6##Y represents COOR₃, R₃ representing hydrogen or an alkyl radicalcontaining 1 to 4 carbon atoms, ##STR7## R₄ and R₅ representing H or analkyl radical containing 1 to 4 carbon atoms, ##STR8## representing a 5-or 6-membered nonaromatic ring, in which the 2 or 3 atoms which formpart of the ring are carbon and/or oxygen and/or nitrogen atoms,

    * NH.sub.2, NHR.sub.6, NR.sub.6 R.sub.7,

R₆ and R₇ representing an alkyl radical containing 1 to 4 carbon atoms,or capable of forming, with the nitrogen atom, a nonaromatic cyclicamine such as morpholine, piperidine, or pyrrolidine,

on condition that when Y represents NH₂, X is other than ##STR9## u isan integer from 0 to 2, v is an integer from 0 to 2,

p takes the value 0 or 1,

q takes the value 0 or 1, p+q being equal to or greater than 1,

n is an integer ranging from 0 to 10,

m is an integer ranging from 0 to 10,

t is 0 or 1,

the total number of carbon atoms in the chain ##STR10## ranging from 2to 20, and to their physiologically acceptable salts, obtained withorganic or inorganic acids and bases.

The invention also relates to the cis- and trans-isomers of thesecompounds, when X represents CH═CH, and to the optical isomers, when##STR11## or X contains an asymmetric carbon atom, and to thecorresponding racemic mixtures and diastereoisomers when ##STR12## anc Xeach contain an asymmetric carbon atom.

Along compounds of formula I, a preferred group of compounds consists ofthose in which W represents C═O.

These compounds correspond to formula II below: ##STR13## in which R₁,R, R', R", X, Y, Z, m, n, p, q, t and u have the meanings given inconnection with formula I.

Another advantageous group of compounds of the invention consists ofthose of formula I in which W represents CH₂.

These compounds correspond to formula III below: ##STR14## in which R₁,R, R', R", X, Y, Z, m, n, p, q, t and u have the meanings given inconnection with formula I.

Another advantageous group of compounds of the invention consists ofthose of formula I in which W represents CHOH.

These compounds correspond to formula IV below: ##STR15## in which R₁,R, R', R", X, Y, Z, m, n, p, q, t and u have the meanings given inconnection with formula I.

Among compounds of formula II, an advantageous group of compoundsconsists of those in which Z represents: ##STR16##

These compounds correspond to formula V below: ##STR17## in which R₁,R₂, R, R', R", X, Y, m, n, p, q, t, u and v have the meanings given inconnection with formula I.

Among compounds of formula V, an advantageous group of compounds of theinvention consists of those in which Y represents --COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms.

Among compounds of formula V, another advantageous group of compounds ofthe invention consists of those in which Y represents NH₂, NHR₆, NR₆ R₇,R₆ and R₇ representing an alkyl radical containing 1 to 4 carbon atoms,or capable of forming, with the nitrogen atom, a nonaromatic cyclicamine such as morpholine, piperidine or pyrrolidine,

on condition that when Y represents --NH₂, X is other than ##STR18##

Among compounds of formula V, an advantageous group of compounds of theinvention consists of those in which p+q equals 1, i.e. compounds whichconsist of a single chain; in the case where p=1, these compoundscorrespond to formula Va below: ##STR19## in which R₁, R₂, R, R', R", X,Y, n, m, u, t and v have the meanings given in connection with formulaI.

Among compounds of formula Va, an advantageous group of compounds of theinvention consists of those in which:

u+v is equal to or greater than 1,

the total number of carbon atoms in the chain ##STR20## is equal to orgreater than 5.

Among compounds of formula V, an advantageous group of compounds of theinvention consists of those in which:

p=1,

q=1,

u+v is equal to or greater than 1,

the total number of carbon atoms in the chains ##STR21## is equal to orgreater than 5

These compounds correspond to formula Vb below: ##STR22## in which R₁,R₂, R, R', R", X, Y, u, v, n, m and t have the meanings given inconnection with formula I.

Among compounds of formula I, an advantageous group of compounds of theinvention consists of those in which p+q equals 1, i.e. compounds whichconsist of a single chain; in the case where p=1, these compoundscorrespond to formula VI below: ##STR23## in which R₁, R, R', R", X, Y,Z, W, m, n, t and u have the meanings given in connection with formulaI.

Among compounds of formula VI, an advantageous group of compounds of theinvention consists of those in which the side chain is in themeta-position relative to W.

These compounds correspond to formula VII below: ##STR24## in which R₁,R, R', R", X, Y, Z, W, m, n, t and u have the meanings given inconnection with formula I.

Among compounds of formula VII, an advantageous group of compounds ofthe invention consists of those in which Y represents COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms.

Among compounds of formula VII in which Y represents COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms, oneadvantageous group of compounds consists of those in which W representsC═O.

These compounds correspond to formula VIII below: ##STR25## in which R₁,R₃, R, R', R", X, Z, m, n, t and u have the meanings given in connectionwith formula I.

Among compounds of formula VII in which Y represents COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms, anadvantageous group of compounds consists of those in which W representsCH₂.

These compounds correspond to formula IX below: ##STR26## in which R₁,R₃, R, R', R", X, Z, m, n, t and u have the meanings given in connectionwith formula I.

Among compounds of formula VII in which Y represents COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms, anadvantageous group of compounds consists of those in which W representsCHOH.

These compounds correspond to formula X below: ##STR27## in which R₁, R₃R, R', R", X, Z, m, n, t and u have the meanings given in connectionwith formula I.

Among compounds of formula VIII, an advantageous group of compoundsconsists of those in which the total number of carbon atoms in the chain##STR28## is equal to or greater than 5.

Among compounds of formula IX, an advantageous group of compoundsconsists of those in which the total number of carbon atoms in the chain##STR29## is equal to or greater than 5.

Among compounds of formula X, an advantageous group of compoundsconsists of those in which the total number of carbon atoms in the chain##STR30## is equal to or greater than 5.

Among compounds of formula VII in which Y represents COOR₃, R₃representing H or an alkyl radical containing 1 to 4 carbon atoms,another advantageous group of compounds consists of those in which:

Z represents ##STR31## the total number of carbon atoms in the chain##STR32## is equal to or greater than 5.

These compounds correspond to formula XI below: ##STR33## in which R₁,R₃, R, R', R", X, W, m, n, t and u have the meanings given in connectionwith formula I.

Among the compounds of formula VI, an advantageous group of compounds ofthe invention consists of those of formula VIbis: ##STR34## in which R₁and R₂ represent a halogen, u and v vary from 0 to 2, W represents C=O,CHOH or CH₂ and n varies from 3 to 11.

Among the compounds of formula VI, an advantageous group of compoundsconsists of those of the following formula VIter: ##STR35## in which R₁represents a halogen, u varies from 0 to 2, W represents C═O, CHOH orCH₂ and n varies from 3 to 11.

Particularly advantageous compounds of the invention correspond to thefollowing formulae: ##STR36##

PREPARATION OF THE COMPOUNDS OF THE INVENTION

The compounds of the invention corresponding to formula I: ##STR37## inwhich W, Z, R₁, R, R', R", X, Y, m, n, p, t and q have the meaningsgiven above, may be prepared:

by subjecting a compound of formula: ##STR38## in which:

A has the meanings given for R₁, except NH₂, i.e. A represents Cl, F,Br, NO₂, CF₃, an alkyl radical containing 1 to 4 carbon atoms,especially methyl or ethyl, an alkoxy radical containing from 1 to 4carbon atoms, acetamido or benzamido, and preferably Cl or NO₂,

Z represents ##STR39##

B has the meanings given in the case of R₂, except NH₂, i.e. Brepresents Cl, F, Br, NO₂, CF₃, an alkyl radical containing 1 to 4carbon atoms, especially methyl or ethyl, an alkoxy radical containing 1to 4 carbon atoms, acetamido or benzamido, and preferably Cl or NO₂,

u, v, p and q have the meanings given above, to a reduction, ifrequired, especially using aluminium chloride and lithium aluminiumhydride in order to reduce --C=O to CH₂, and obtain the compound offormula: ##STR40## in which A, Z, u, p and q have the meanings givenabove,

by then subjecting the amino compound of formula given above toSandmeyer reaction (formation of the diazonium salt and action ofsulphur dioxide), to obtain a sulphohalide, especially sulphochloride offormula: ##STR41## in which A, Z, u, p and q have the meanings givenabove and W' represents C═O or CH₂,

by then reacting the sulphohalide, especially the sulphochloride, offormula given above, with one compound of formula: ##STR42## in which:

R represents H, an alkyl radical containing 1 to 6 carbon atoms or abenzyl radical,

R' and R" represent H or an alkyl radical containing 1 to 4 carbonatoms,

X represents (CH₂)_(r), r taking the value of O or 1, --CH═CH--,##STR43##

Y represents COOR₃, R₃ representing H or an alkyl radical containing 1to 4 carbon atoms, ##STR44## R₄ and R₅ representing H or an alkylradical containing 1 to 4 carbon atoms, ##STR45## representing a 5- or6-membered nonaromatic ring, in which the 2 or 3 atoms which form partof the ring are carbon and/or oxygen and/or nitrogen atoms,

    * NH.sub.2, NHR.sub.6, NR.sub.6 R.sub.7,

R₆ and R₇ representing an alkyl radical containing 1 to 4 carbon atomsor capable of forming, with the nitrogen atom, a nonaromatic cyclicamine such as morpholine, piperidine or pyrrolidine,

on condition that when Y represents NH₂, X is other than ##STR46##

n is an integer ranging from 0 to 10,

m is an integer ranging from 0 to 10,

t is 0 or 1,

the total number of atoms in the chain ##STR47## ranging from 2 to 20,in order to obtain the compound of formula: ##STR48##

and in the case where W' represents C═O, by subjecting, if required, theabove compound to a reduction, expecially using an alkali metalborohydride, such as sodium borohydride, in order to reduce C═O to CHOH,

by then carrying out a reduction, if required, when A and/or Brepresent(s) NO₂.

Compounds of the invention of formula II: ##STR49## in which R₁, R, R',R", X, Y, Z, m, n, p, q, t and u have the meanings given above, mays beprepared by reacting a sulphohalide, especially a sulphochloride offormula: ##STR50## in which A, Z and u have the meanings given above ora disulphohalide, especially a disulphochloride of formula: ##STR51## inwhich A, u and Z have the meanings given above, with one or twocompounds of formula: ##STR52## in which R, R', R", n, m, t, X and Yhave the meanings given above,

followed, if required, by a reduction when A and/or B represent(s) NO₂.

Compounds of the invention of formula II may be prepared:

by esterifying a compound as obtained above, and in which Y representsCOOH, into a compound of formula II in which Y represents COR₃, R₃representing an alkyl radical containing 1 to 4 carbon atoms,

or by carrying out a reaction suitable for converting a compound asobtained above and in which Y represents COOH into a compound of formulaII in which Y represents: ##STR53## R₄ and R₅ representing H or an alkylradical containing 1 to 4 carbon atoms, ##STR54##

The preparation of the compounds of the invention in which Y represents:##STR55##

R₄ and R₅ representing an alkyl group containing 1 to 4 carbon atoms,##STR56## representing a 5- or 6-membered nonaromatic ring in which the2 or 3 atoms which form part of the ring are carbon and/or oxygen and/ornitrogen atoms, is carried out using compounds in which Y representsCOOH, according to conventional methods, for example, as mentionedbelow:

The conversion of an acid ##STR57## to an amide may be carried outespecially according to two methods:

The first of these methods consists:

1) in preparing an acid chloride intermediate according to the reactionscheme below: ##STR58## 2) and then in reacting an amine with the acidchloride, in the presence of an acceptor for hydrochloric acid, forexample a tertiary amine according to the reaction scheme below:

In the first stage, PCl₃ or PCl₅ may also be used instead of SOCl₂.

The second method consists:

1) in preparing an ester intermediate according to the reaction schemebelow: ##STR59## H⁺ advantageously originating from HCl or HBr, and 2)in reacting an amine, preferably under pressure and at a hightemperature, according to the reaction scheme below: ##STR60##

These two methods may be used for the preparation of primary, secondaryand tertiary amides, depending on the amine used at the start.

The conversion of an amide group to a nitrile group may be carried outaccording to two methods.

The first of these methods consists in reacting a dehydrating geagent(phosphorus oxychloride POCl₃, phosphorus pentoxide P₂ O₅ or thionylchloride SOCl₂) with an amide ##STR61## according to the reaction schemebelow: ##STR62##

The second method consists in carrying out a pyrolysis of the amide athigh temperature, for example at approximately 200° C.: ##STR63##

In this case, R may represent either the sulphonamide derived fromdiarylmethane of formula I, in which Y represents CONH₂ or the aminatedchain, subsequently condensed with the sulphochloride in order to avoiddegradations.

The conversion of the nitrile group to a tetrazole group may be carriedout by the cyclocondensation of nitrile with sodium azide according tothe reaction scheme below: ##STR64##

The conversion of an amide into a cyclic compound such asdihydroimidazole or tetrahydropyrimidine may be carried out by a secondmethod which consists in preparing a thioamide intermediate according tothe reaction scheme below: ##STR65##

(In this case, R may represent either the sulphonamide derived romdiarylmethane of formula I, in which Y represents CONH₂, or the aminatedchain, subsequently condensed with the sulpochloride in order to avoiddegradations), and then in preparing an isothiouronium compoundaccording to the reaction scheme below: ##STR66## and then in cyclinzingwith a diamine according to the reaction scheme below: ##STR67##

The conversion of an acid ##STR68## to an imidazole ring may be carriedout by the direct condensation of ethylenediamine with the acidaccording to the reaction scheme below: ##STR69##

Compounds of the invention of formula II, in which Y represents NH₂,NHR₆ or R₆ and R₇ representing an alkyl radical containing 1 to 4 carbonatoms, or forms, with nitrogen, a nonaromatic cyclic amine such asmorpholine, piperidine or pyrrolidine, may be prepared by reacting asulphohalide, especially sulpochloride of formula: ##STR70## in which:

A represents R₁, except NH₂, i.e. Cl, F, Br, NO₂, CF₃, an alkyl radicalof 1 to 4 carbon atoms, an alkoxy radical containing 1 to 4 carbonatoms, acetamido or benzamido,

Z represents: ##STR71##

B has the meanings given in the case of R₂, except NH₂, i.e. Brepresents Cl, Br, F, NO₂, CF₃, an alkoxy or alkyl radical containing 1to 4 carbon atoms, acetamido or benzamido and preferably cl o NO₂,

u represents an integer from 0 to 2,

v represents an integer from 0 to 2, or a disulphohalide, especiallydisulphochloride of formula: ##STR72## in which A, u, Z have themeanings given above, with one of formula: ##STR73## in which:

R represents H, an alkyl radical containing 1 to 6 carbon atoms or abenzyl radical,

R' and R" represent H or an alkyl radical containing 1 to 4 carbonatoms,

n represents an integer ranging from 0 to 10,

m represents an integer ranging from 0 to 10,

t is 0 or 1,

X has the meaning above mentioned,

Y having the meaning NH₂, NHR₆ or NR₆ R₇, as defined above.

The compounds above in which R₁ and/or R₂ represent(s) NH₂ are preparedby the reduction of compounds in which A and/or B represent(s) NO₂, bycatalytic hydrogenation or by chemical reduction.

The reaction described above relating to sulphochlorides can also beapplied to other sulphohalides, especially to sulphobromides.

An advantageous method for the preparation of the compounds of theinvention in which Y represents NH₂, NHR₆ or NR₆ R₇, as defined above,consists in carrying out the reaction as given below, by way of generalexample.

0.1 mole of a tertiary amine (such as triethylamine, pyridine and thelike) is added, with stirring, to 0.1 mole of (aroyl)phenylsulphonylchloride dissolved in an organic solvent (ethyl ether, methylenechloride, chloroform and the like) which is cooled in an ice bath, and0.1 mole of aminoalkylamines dissolved in the same organic solvent isadded slowly.

After approximately 12 hours of contact, the reaction medium is broughtto ambient temperature, while still being stirred, and is filtered; thefiltrater is evaporated to dryness and then taken up with water.

The product obtained is:

either in the form of crystals which are washed with water, drained,dried and then recrystallized in a suitable solvent, or in the form ofan oil which is either crystallized directly in a solvent or is, afterextraction with an organic solvent (especially ether, ethyl acetate,methylene chloride, or chloroform), drying and evaporation, purified bysilica column chromatography and then crystallized in a suitablesolvent. ##STR74## are prepared as follows:

One equivalent of disulphochloride is used as the starting material andit is condensed with at least two equivalents of suitable amino acid oraminoalkylamine.

One group of sulphochlorides advantageously used in the preparation ofthe compounds of the invention corresponding to formula II consists of:

2-benzoyl-4-nitrobenzenesulphonyl chloride

2-benzoyl-4-chlorobenzenesulphonyl chloride

4-chloro-2-(2-chlorobenzoyl)benzenesulphonyl chloride

2-benzoylbenzenesulphonyl chloride

2-(4-chlorobenzoyl)benzenesulphonyl chloride

4-benzoylbenzenesulphonyl chloride

3-benzoylbenzenesulphonyl chloride

3-(2,4-dichlorobenzoyl)-4-chlorobenzensulphonyl chloride

3-benzoyl-4-chlorobenzenesulphonyl chloride3-(4-chlorobenzoyl)-4-chlorobenzenesulphonyl chloride4-benzoyl-3-chlorobenzenesulphonyl chloride and4-chloro-3-(2-thienoyl)benzenesulphonyl chloride.

One group of amino acids advantageously used in the preparation of thecompounds of the invention of formula II consists of:

    NH.sub.2 (CH.sub.2).sub.n - COOH

n varying from 1 to 11.

One group of dialkylaminoalkylamines advantageously used in thepreparation of compounds of formula II of the invention consists of:##STR75## R₆ and R₇ representing an alkyl group of 1 to 4 carbon atomsor forming a morpholine group with the nitrogen atom.

Compounds of the invention of formula III: ##STR76## in which R₁, R, R',R", X, Y, Z, m, n, p, q, t and u have the meanings given above may beprepared by subjecting the compound of formula: ##STR77## or of formula:##STR78## to a reduction, especially using aluminium chloride andlithium aluminium hydride, in order to reduce C═O to CH₂ and to obtainthe compound of formula: ##STR79## by subjecting one of these compoundsto Sandmeyer reaction (formation of the diazonium salt and action ofsulphur dioxide) to obtain compounds of formula: ##STR80## and then bycondensing the sulphohalide or the disulphohalide of formula givenabove, with one compound of formula: ##STR81## in which R, R', R", X, Y,n, m and t have the meanings given above, followed, if required, by areduction when A and/or B represent(s) NO₂.

One group of amino acids or of dialkylaminoalkylamines advantageouslyused for the preparation of the compounds of formula III is chosen fromamongst: ##STR82## R₆ and R₇ representing an alkyl group of 1 to 4carbon atoms or forming a morpholine group with the nitrogen atom.

The compounds of formula: ##STR83## preferred for the preparation of thecompounds of formula III are chosen from amongst:

3-(2,4-dichlorobenzyl)-4-chlorobenzenesulphonyl chloride

3-(4-chlorobenzyl)-4-chlorobenzenesulphonyl chloride

2-benzyl-4-chlorobenzenesulphonyl chloride

2-(2,4-dichlorobenzyl)-4-chlorobenzenesulphonyl chloride

2-(4-chlorobenzyl)-4-chlorobenzenesulphonyl chloride

4-benzyl-3-chlorobenzenesulphonyl chloride

4-(2,4-dichlorobenzyl)-3-chlorobenzenesulphonyl chloride

4(4-chlorobenzyl)-3-chlorobenzenesulphonyl chloride and

3-benzyl-4-chlorobenzenesulphonyl chloride.

Compounds of the invention of formula IV: ##STR84## in which R₁, R, R',R", X, Y, Z, m, n, p, q, t and u have the meanings given above, may beprepared by subjecting the compound of formula II: ##STR85## in which A,X, Y, Z, R, R', R", m, n, p, q, t and u have the meanings given above,and obtained as above, before the reduction, when required, of A and/orB when they represent NO₂, to a reduction to convert C═O into CHOH,using an alkali metal borohydride, especially sodium borohydride.

One group of amino acids or of dialkylaminoalkylamines advantageouslyused for the preparation of compounds of formula IV is chosen fromamongst: ##STR86## R₆ and R₇ representing an alkyl group of 1 to 4carbon atoms or forming a morpholine group with the nitrogen atom.

The sulphochlorides advantageously used for the preparation of thecompounds of formula IV are chosen from amongst:

2-benzoyl-4-nitrobenzenesulphonyl chloride

2-benzoyl-4-chlorobenzenesulphonyl chloride

4-chloro-2-(2-chlorobenzoyl)benzenesulphonyl chloride

2-benzoylbenzenesulphonyl chloride

2(4-chlorobenzoyl-benzenesulphonyl chloride

4-benzoylbenzenesulphonyl chloride

3-benzoylbenzenesulphonyl chloride

3(2,4-dichlorobenzoyl)-4-chlorobenzenesulphonyl chloride

3-benzoyl-4-chlorobenzenesulphonyl chloride

3-(4-chlorobenzoyl)-4-chlorobenzenesulphonyl chloride

4-benzoyl-3-chlorobenzenesulphonyl chloride and

4-chloro-3-(2-thenoyl)benzenesulphonyl chloride.

Compounds of the invention corresponding to formula V below: ##STR87##in which R₁, R₂, R, R', R", X, Y, m, n, p, q, t, u and v have themeanings given above, may be prepared by reacting a sulphohalide,especially a sulphochloride of formula: ##STR88## in which A, B, p, q, uand v have the meanings given above, or a disulphohalide, especially adisulphochloride of formula: ##STR89## in which A, B, p, q, u and v havethe meanings given above with one compound of formula: ##STR90## inwhich R, R', R", m, n, t, X and Y have the meanings given above,followed, if required, by a reduction when A and/or B represent(s) NO₂.

Compounds of formula V in which:

Y represents COOH

may be prepared by reacting a sulphochloride of formula Vquater, withone amino acid of formula: ##STR91## in which R, R', R", n, m, t and Xhave the meanings given above.

Compounds in which Y represents COOR₃ (R₃ being different from H),especially COOC₂ H₅, may be prepared by the esterification of compoundsof the invention in which Y represents --COOH.

Compounds of the invention of formula V, in which Y represents COOR₃, R₃representing H or an alkyl group containing 1 to 4 carbon atoms, and inwhich R₁ represents NH₂ and/or R₂ represents NH₂, are prepared byreducing compounds in which A represents NO₂ and/or B represents NO₂, bycatalytic hydrogenation or by chemical reduction.

The reaction described above for the sulphochlorides may also be appliedto other sulphohalides, especially sulphobromides.

The compounds of the invention, especially those of formula V, in whichY represents COOR₃, R₃ representing H or an alkyl radical containing 1to 4 carbon atoms, are advantageously prepared by the followingprocedure, given by way of general example:

0.2 mole of amino acid dissolved in 4 equivalents of an aqueous basicsolution (for example caustic soda, caustic potash or ammonia) is addedto 0.1 mole of (aroyl)phenylsulphonyl chloride dissolved in an organicsolvent which has a very low solubility in water (for example ethylether, methylene chloride or chloroform).

The reaction medium is stirred vigorously until the sulphochloridedisappears (as tested by thin layer chromatography or by gaschromatography).

After removing the organic phase, the pH of the aqueous phase isadjusted to approximately 1 to 3 by adding an aqueous 1 N to 10 N,preferably 5 N, acid solution (for example hydrochloric acid orsulphuric acid).

So, the product obtained is:

either in the form of crystals which are drained and then dried beforebeing recrystallized in a suitable solvent,

or in the form of an oil, which is either crystallized directly in asolvent or is, after extracting with an organic solvent (especiallyether, ethyl acetate, methylene chloride or chloroform), drying andevaporation, purified by silica column chromatography and thencrystallized directly in a suitable solvent.

The compounds of the invention of formula VI: ##STR92## in which R₁, R,R', R", X, Y, Z, W, m, n, t and u have the meanings given above may beprepared by subjecting a compound of formula: ##STR93## in which A, Zand u have the meanings given above, if required, to a reduction,especially using aluminium chloride and lithium aluminium hydride toreduce C═O to CH₂, and to obtain the compound of formula: ##STR94## inwhich A, Z and u have the meanings given above,

by then subjecting one of the amino compounds of formula given above toSandmeyer reaction (formation of the diazonium salt and action ofsulphur dioxide), to obtain a sulphohalide of formula: ##STR95## inwhich A, Z and u have the meanings given above and W' represents C═O orCH₂,

by reacting the sulphohalide, especially the sulphochloride, of formulagiven above, with one compound of formula: ##STR96## in which R, R', R",m, n, t, X and Y have the meanings given above,

to obtain the compounds of formula: ##STR97## and in the case where W'represents C═O, by subjecting, if required, the above compound to areduction, especially using an alkali metal borohydride such as sodiumborohydride, to reduce C═O into CHOH,

by then carrying out a reduction, if required, when A and/or Brepresent(s) NO₂.

The compounds of the invention of formula VII: ##STR98## in which R₁, R,R', R", X, Y, Z, W, m, n, t and u have the meanings given above, may beprepared by subjecting a compound of formula: ##STR99## in which A, Zand u have the meanings given above, if required, to a reduction,especially using aluminium chloride and lithium aluminium hydride toreduce C═O to CH₂, and to obtain the compound of formula: ##STR100## inwhich A, Z and u have the meanings given above,

by then subjecting one of the amino compounds of formula given above toSandmeyer reaction (formation of the iazonium salt and action of sulphurdioxide), to obtain a sulphohalide of formula: ##STR101## in which A, Zand u have the meanings given above and W' represents C═O or CH₂,

by reacting the sulphohalide, especially the sulphochloride, of formulagiven above, with one or two compounds of formula: ##STR102## in whichR, R', R", X, Y, m, n and t have the meanings given above,

to obtain the compound of formula: ##STR103##

and in the case where W' represents C═O, by subjecting, if required, theabove compound to a reduction, especially using an alkali metalborohydride, such as sodium borohydride, to reduce C═O to CHOH,

by then carrying out a reduction, if required, when A and/or Brepresent(s) NO₂.

The compounds of the invention of formula VII, in which:

Y represents COOR₃, R₃ representing H or an alkyl radical containing 1to 4 carbon atoms, may be prepared

by subjecting a compound of formula: ##STR104## in which A, Z and u havethe meanings given above, if required, to a reduction, especially usingaluminium chloride and lithium aluminium hydride to reduce C═O to CH₂,and to obtain the compound of formula: ##STR105## in which A, Z and uhave the meanings given above,

by then subjecting one of the amino compounds of formula given above toSandmeyer reaction (formation of the diazonium salt and action ofsulphur dioxide), to obtain a sulphahalide of formula: ##STR106## inwhich A, Z and u have the meanings given above and W' represents C═O orCH₂,

by reacting the sulphohalide, especially the sulphochloride, of formulagiven above, with one or two compounds of formula: ##STR107## in whichR, R', R", X, R₃, m, n and t have the meanings given above, to obtainthe compound of formula: ##STR108##

and in the case where W' represents C═O, by subjecting, if required, theabove compound to a reduction, especially using an alkali metalborohydride, such as sodium borohydride, to reduce C═O to CHOH,

by then carrying out a reduction, if required, when A and/or Brepresent(s) NO₂.

The compounds of formula VIII, IX and X corresponding to the compoundsof formula VII in which Y represents COOR₃, R₃ representing H or analkyl group containing 1 to 4 carbon atoms, and in which W representsC═O (compounds of formula VIII), CH₂ (compounds of formula IX) and CHOH(compounds of formula X) respectively, are prepared by following theprocedure given in the case of compounds of formula VII, in which Yrepresents COOR₃ using appropriate intermediate compounds.

The compounds of the invention of formula XI: ##STR109## in which:

the total number of carbon atoms in the chain ##STR110## is equal to orgreater than 4, and in which:

R₁, R₃, R, R', R", X, W, m, n, t and u have the meanings given above,may be prepared by subjecting the compound of formula: ##STR111## inwhich:

A and u have the meanings given above, if required, to a reduction,especially using aluminium chloride and lithium aluminium hydride toreduce C═O to CH₂, and to obtain the compound of formula: ##STR112## inwhich A and u have the meanings given above,

by then subjecting the amino compound of formula given above toSandmeyer reaction (formation of the diazonium salt and action ofsulphur dioxide), to obtain a sulphohalide of formula (A) ##STR113## inwhich A and u have the meanings given above and W' represents C═O orCH₂,

by the reacting the sulphohalide, especially the sulphochloride, offormula given above, with a compound of formula: ##STR114## in which R,R', R", X, m, n, t and R₃ have the meanings given above,

to obtain the compound of formula: ##STR115##

and in the case where W' represents C═O, by subjecting, if required, theabove compound to a reduction, especially using an alkali metalborohydride, such as sodium borohydride, to reduce C═O into CHOH,

by then carrying out a reduction, if required, when A and/or Brepresent(s) NO₂.

The sulphochlorides used in the preparation of the compounds of theinvention may be prepared according to conventional processes.

The sulphochlorides which lead to compounds of the invention in whichthe side chain is in the orthoposition relative to C═O may be preparedby using optionally substituted 2-nitrobenzophenone, which is reduced bya known method into optionally substituted 2-aminobenzophenone, which isconverted into sulphohalide, especially into 2-benzoylbenzenesulphonylchloride, by a Sandmeyer reaction.

The sulphochlorides which lead to compounds of the invention in whichthe side chain is in the meta- or in the para- position relative to C═Oare prepared by following the procedure given above using appropriatestarting products.

The isulphochlorides are prepared starting with the correspondingdiamino compounds by a Sandmeyer reaction which consists in:

1) diazotization with nascent nitrous acid (NaNO₂, HCl or NaNO₂, formicacid or NaNO₂, acetic acid),

2) adding the diazonium salt to a saturated solution of sulphur dioxidedissolved in acetic acid in the presence of cupric chloride.

The iamines listed below are prepared according to procedures given inthe literature:

2-aminophenyl-3-aminophenylketone

described in CA 61 7186e

2-aminophenyl-4-aminophenylketone

described in CA 44 2960g from the corresponding dinitro compound,reduced chemically

described in CA 61 7186e

3-aminophenyl-3-aminophenylketone

described in CA 43 3136e, 8061e, CA 61 7186e.

The thenoylbenzenesulphonyl chlorides are prepared according to thetechnique of G. Holt and B. Padgin, J. Chem. Soc. 1960, 2508, by theFriedel and Crafts reaction:

either by starting directly with a chlorosulphonylated benzoyl chlorideby reacting the thiophene in the presence of aluminium chloride,

or by starting with a nitrobenzoyl chloride which is reacted with thethiophene in the presence of aluminium chloride, thenitrodiarylketoneobtained then being reduced chemically or catalytically into aminodiarylketone which, after a Sandmeyer reaction, gives the sulphochlorideexpected.

The following examples, which relate to the preparation of a number ofsulphochlorides and of new compounds of the invention, are given toillustrate the invention, without implied limitation.

EXAMPLE 1 Preparation of 2-benzoyl-4-nitrobenzenesulphonyl chloride

72.6 g (0.3 mole) of 2l-amino-5-nitrobenzophenone are added to a mixtureof 225 ml of a solution of hydrochloric acid (d=1.18) and 75 ml of pureacetic acid, in small portions. The reaction medium is stirred and thencooled to approximately -5° C. and maintained at this temperature whileadding, drop by drop, a solution of sodium nitrite (21.75 g in 75 ml ofwater).

When the addition is complete, the reaction medium is stirred at -5° C.for 45 minutes, and then filtered.

The filtrate is added, in portions, to a saturated solution of sulphurdioxide in acetic acid (750 ml) which is cooled to 0° Celsius andcontains 16.5 g of cupric chloride.

The mixture, having been vigorously stirred for 3 hours, is poured ontocrushed ice. The sulphochloride precipitate is dried, washed severaltimes with water and then dried under vacuum.

The product (62.5 g) is crystallized in a benzene-cyclohexane mixture.It has the empirical formula: C₁₃ H₈ ClNO₅ S (325.71); yield: 65%; m.p.161° C.

This compound is a new product.

EXAMPLE 2 Preparation of 4-chloro-2-(2-chlorobenzoyl)benzenesulphonylchloride

The reaction is carried out as described above in Example 1, using2-amino-5-chlorophenyl-2-chlorophenylketone as the starting product.

The characteristics of the product obtained are as follows:

C₁₃ H₇ Cl₃ O₃ S (349.61); yield 58%; m.p. 100° C.

This compound is a new product.

EXAMPLE 3 Preparation of 2-benzoylbenzenesulphonyl chloride

The reaction is carried out as described above in Example 1, using2-aminobenzophenone as the starting product.

The characteristics of the product obtained are as follows:

C₁₃ H₉ CLO₃ S (280.72); yield 30%; m.p. 99° C.

EXAMPLE 4 Preparation of 2-(4-chlorobenzoyl)benzenesulphonyl chloride

The reaction is carried out as described above in Example 1, using2-aminophenyl-4-chlorophenylketone as the starting product.

The product obtained has the following characteristics:

C₁₃ H₈ Cl₂ O₃ S (315.17); yield 53%; m.p. 70° C.

EXAMPLE 5 Preparation of 4-benzoylbenzenesulphonyl chloride

The reaction is carried out as described above in Example 1, using4-aminobenzophenone.

The characteristics of the product obtained are as follows:

C₁₃ H₈ Cl₄ O₃ S (280.72); yield: 70%; m.p. 90° C.

EXAMPLE 6 Preparation of a compound of the invention in which the sidechain is acid 11-(2-benzoyl-4-chlorobenzenesulphonamido)undecanoic acid(compound No. 1572).

24.16 g (0.12 mole) of 11-aminoundecanoic acid in 250 ml of normalcaustic soda are added to 37.9 g (0.12 mole) of2-benzoyl-4-chlorobenzenesulphonyl chloride in 250 ml of methylenechloride, at 0° C. and with stirring.

After stirring for 6 hours at ambient temperature, the organic phase isremoved. The pH of the aqueous phase is adjusted to 2 by adding a 2 Nhydrochloric acid solution.

After extracting with ethyl acetate, washing the organic phase withwater, drying over sodium sulphate and evaporating under reducedpressure, the residue is crystallized in petroleum ether to give 44.5 gof white crystals with a melting point of 70° C.

The reaction yield is 77.2%.

EXAMPLE 7 Preparation of a compound of the invention which contains twoacid side chains.

The procedure in Example 6 above is followed, using 2 molecules of aminoacid for 1 molecule of sulphochloride.

EXAMPLE 8 Preparation of a compound of the invention in which the sidechain is aminated. (Compound No. 1344):2-benzoyl-4-chloro-N-(3-morpholinopropyl)benzenesulphonamide.

7.5 ml of redistilled triethylamine are added to 4.72 g (0.015 mole) of2-benzoyl-4-chlorobenzenesulphonyl chloride in 45 ml of anhydrousmethylene chloride, and 2.16 g (0.015 mole) of 3-morpholinopropylaminein 10 ml of anhydrous methylene chloride are then added at 0° C.

After stirring for 3 hours at ambient temperature, the precipitate(triethylamine hydrochloride) is drained.

The filtrate is evaporated to dryness under vacuum and taken up with 20ml of water.

The crystals obtained are drained, washed with water until the washingsare free of chloride ions and then dried before being recrystallized ina cyclohexanebenzene (1:1) mixture.

4.93 g of white crystals with a melting point of 116° C. are obtained.The reaction yield is 80%.

EXAMPLE 9 Preparation of 4-[4(2-thenoyl)benzenesulphonamido]butyric acida) Preparation of 4-nitrophenyl-2-thienylketone 15 g of aluminiumchloride, followed by 10 ml of thiophene (0.18 mole), are carefullyadded to 11.14 g (0.06 mole) of 4-nitrobenzoyl chloride in 150 ml ofmethylene chloride. After stirring for 4 hours at ambient temperature,the reaction mixture is poured onto ice. After extracting withdichloromethane, drying the organic phase over sodium sulphate andevaporating under vacuum, the residue is purified by silica columnchromatography using dichloromethane as the eluent.

6.25 g of the nitrated derivative (yellow product), with a melting pointof 172° C., are obtained.

b) Preparation of 4-aminophenyl-2-thienylketone

4-Aminophenyl-2-thienylketone is obtained by catalytic reduction of thenitrated compound above at atmospheric pressure using palladinizedcharcoal (10% palladium) as the catalyst and ethyl acetate as thesolvent.

When the theoretical amount of hydrogen is absorbed, the catalyst isremoved by filtration, the organic phase is evaporated to dryness, andthe residue is taken up with a 2 N hydrochloric acid solution.

The pH of the acid aqueous phase which is washed with ether is then madealkaline. The crystals obtained corresponding to the product expectedhave a melting point of 120° C.

c) Preparation of 4-(2-thenoyl)benzenesulphonyl chloride

The procedure used is that described above for the Sandmeyer reaction(Example 1).

Starting with 609 mg (3.10⁻³ mole) of 4-aminophenyl-2-thienylketone, 400mg of 4-(2-thenoyl)benzenesulphonyl chloride are obtained in the form ofcrystals with a melting point of 118° C.

d) Preparation of 4-[4-(2-thenoyl)benzenesulphonamido]butyric acid

103 mg (1.10⁻³ mole) of 4-aminobutyric acid dissolved in 4 ml of a 0.5 Nsolution of caustic soda are added dropwise to 287 mg (1.10⁻³ mole) of4-(2-thenoyl)benzenesulphonyl chloride in 5 ml of ethyl ether.

After stirring for 2 hours at ambient temperature, the organic phase isremoved by decantation. The pH of the aqueous phase is adjusted to 2 byadding a 4 N solution of hydrochloric acid.

The crystals are drained, and then washed with the minimum amount ofwater until the washings are free of Cl⁻ ions.

After drying under vacuum, the crystals obtained (200 mg) have a metingpoint of 128°-130° C.

The compounds of Table I below were prepared according to the processdescribed in Example 6.

EXAMPLE 10 Preparation of3-(2,4-dichlorobenzoyl)-4-chlorobenzenesulphonyl chloride a)Preparationof 2,2',4'-trichloro-5-nitrobenzophenone

6 g of aluminium chloride are added to 5 g of 2-chloro-5-nitrobenzoylchloride in 60 ml of dichloromethane, and 30 ml of 1,3-dichlorobenzeneare then added dropwise. The reaction medium is heated for 2 hours at80° C. and then cooled, and poured onto crushed ice. After extractingwith dichloromethane, washing with water and drying over sodiumsulphate, the organic phase is evaporated to dryness under vacuum andthe crystalline residue is recrystallized in cyclohexane (3.6 g).

C₁₃ H₆ Cl₃ NO₃ (330.55); yield: 48%; m.p. 117° C.

b)Preparation of 5-amino-2,2',4'-trichlorobenzophenone

7.5 g of 2,2',4'-trichloro-5-nitrobenzophenone in 100 ml of ethylacetate are hydrogenated at atmospheric pressure and at ambienttemperature in the presence of palladinized charcoal.

After removing the catalyst, the reaction medium is evaporated todryness under vacuum and it gives a crystalline residue weighing 6.6 g.

C₁₃ H₈ Cl₃ NO(300.57); yield: 88%; m.p. 103° C.

c) Preparation of 4-chloro-3-(2,4-dichlorobenzoyl)-benzenesulphonylchloride

The reaction is carried out in the same way as in Example 1.

C₁₃ H₆ Cl₄ O₃ S (384.06; yield: 60%; m.p. 118° C.

EXAMPLE 11 Preparation of 3-benzoyl-4-chlorobenzenesulphonyl chloride a)Preparation of 2-chloro-5-nitrobenzophenone

The reaction is carried out as in Example 10 a) by reacting benzene with2-chloro-5-nitrobenzoyl chloride in the presence of aluminium chloride.

C₁₃ H₈ ClNO₃ (261.66; yield: 55%; m.p. 85° C.

b) Preparation of 5-amino-2-chlorobenzophenone

The reaction is carried out as in Example 10 b) starting with2-chloro-5-nitrobenzophenone.

c) Preparation of 3-benzoyl-4-chlorobenzenesulphonyl chloride

The reaction is carried out in the same way as in Example 1.

C₁₃ H₈ Cl₂ O₃ S (315.14); yield 40%; m.p. 92° C.

EXAMPLE 12 Preparation of 3-(4-chlorobenzoyl)-4l -chlorobenzenesulphonylchloride a) Preparation of 2,4-dichloro-5-nitrobenzophenone

The reaction is carried out as in Example 10 a) by reactingchlorobenzene with 2-chloro-5-nitrobenzoyl chloride in the presence ofaluminium chloride.

C₁₃ H₇ Cl₂ NO₃ (296.11); yield: 76%; m.p. 92° C.

b) Preparation of 5-amino-2,4'-dichlorobenzophenone

The reaction is carried out as in Example 10 b) starting with2,4'-dichloro-5-nitrobenzophenone.

c) Preparation of 3-(4-chlorobenzoyl)-4-chlorobenzenesulphonyl chloride

The reaction is carried out as in Example 1.

C₁₃ H₇ Cl₃ O₃ S (349.62); yield: 65%; m.p. 110° C.

EXAMPLE 13 Preparation of 4-benzoyl-3-chlorobenzenesulphonyl chloride

The reaction is carried out as in Example 10 a)

a) Preparation of 2-chloro-4-nitrobenzophenone by reacting benzene with2-chloro-4-nitrobenzoyl chloride in the presence of aluminium chloride.

C₁₃ H₈ ClNO₃ (261.66); yield: 75%; m.p. 90° C.

b) Preparation of 4-amino-2-chlorobenzophenone

The reaction is carried out in the same way as in Example 10 b).

c) Preparation of 4-benzoyl-3-chlorobenzenesulphonyl chloride

The reaction is carried out in the same way as in Example 10 c).

EXAMPLE 14 Preparation of 4-chloro-3-(2-thenoyl)benzenesulphonylchloride a) Preparation of 2-chloro-5-nitrophenyl-2-thienylketone

The reaction is carried out as mentioned in Example 9 a) startng with2-chloro-5-nitrobenzoyl chloride. C₁₁ H₆ ClNO₃ S (267.69); yield: 85%;m.p. 105°-106° C.

b) Preparation of 5-amino-2-chlorophenyl-2-thienylketone hydrochloride

The reaction is carried out as mentioned in Example 9 b).

C₁₁ H₈ ClNOS, HCl (274.17); yield: 95%; m.p. 115°-120° C.

c) Preparation of 4-chloro-3-(2-thenoyl)benzenesulphonyl chloride

The reaction is carried out as mentioned in Example 1.

C₁₁ H₁₆ Cl₂ O₃ S₂ (321.20); yield: 72%; m.p. 84° C.

EXAMPLE 15 Preparation of12-[3-(4-chlorophenylhydroxymethyl)-benzenesulphonamido]dodecanoic acidIC-1810

1.1 g of sodium borohydride are added in small portions to 4.8 g of12-(3-benzoyl-4-chlorobenzenesulphonamido)dodecanoic acid in 200 ml ofabsolute ethanol, maintaining the temperature between 0° and 5° C. Afterstirring for 2 hours at ambient temperature, the reaction medium isneutralized by adding ethanolic hydrogen chloride and then evaporated todryness under vacuum. The residue is taken up with ethyl acetate, theorganic phase is washed with water, dried over sodium sulphate and thenevaporated to dryness under vacuum. The product is obtained in the formof crystals (4g).

C₂₅ H₃₄ ClNOS₅ S (490.02); yield: 63%; m.p. 122° C.

The compounds IC-1796 and IC-1807 are prepared by this method.

EXAMPLE 16 11-(3-Benzyl-4-chlorobenzenesulphonamido)undecanoic acidIC-1808 a) Preparation of 3-benzyl-4-chloroaniline

6.8 g of lithium aluminium hydride, followed by 44.4 g of aluminiumchloride and then 22 g of 5-amino-2-chlorobenzophenone dissolved inanhydrous ether are added in small amounts, under a nitrogen atmosphere,into 1000 ml of anhydrous ether which is cooled to 0° C. After stirringfor 2 hours and under reflux, the excessive reagents are decomposed byvery slowly adding 7 ml of 15% caustic soda and, finally, 21 ml ofwater. After filtering and washing the precipitate with 2×200 ml ofether, the organic phase is washed, dried over Na₂ SO₄ and thenevaporated to dryness under vacuum.

After purification on a silica column, eluting with a 3:2 hexane:CH₃COOC₂ H₅ mixture, 17 g of the product are isolated in the form of acolourless lacquer.

C₁₃ H₁₂ ClN (217.68); yield: 82%.

b) Preparation of 3-benzyl-4-chlorobenzenesulphonyl chloride

The reaction is carried out as mentioned in Example 1.

C₁₃ H₁₀ Cl₂ O₂ S (301.19); yield: 52%

c) 11-(3-benzyl-4-chlorobenzenesulphonamido)dodecanoic acid

The reaction is carried out as mentioned in Example 6.

C₂₄ H₃₂ ClNO₄ S (467.04); yield: 30%; m.p. 88°-90° C.

The compound IC-1797 is prepared in the same way

Example 17 Preparation of6-(2-benzoyl-4-chlorobenzenesulphonamido)-capronitrile

15 ml of redistilled triethylamine are added to 15.7 g of4-chloro-2-benzoylbenzenesulphonyl chloride in 100 ml of anhydrousdichloromethane, and 5.6 g of 6-aminocapronitrile in 20 ml ofdichloromethane are then added dropwise at 0° C.

After stirring overnight at 20° C., the reaction medium is evaporated todryness under vacuum. The residue is taken up with 100 ml of water andextracted with 2×200 ml of ethyl acetate.

After drying, evaporating to dryness under vacuum and purification on asilica column (CH₂ Cl₂), 19 g of a syrupy product are obtained.

C₁₉ H₁₉ ClN₂ S (390.89); yield: 95%.

EXAMPLE 18 Preparation of ethyl11-(2-benzoyl-4-chlorobenzenesulphonamido)undecanoate IC-1740

7 ml of anhydrous triethylamine are added to 5.3 g of ethyl11-aminoundecanoate hydrochloride in 30 ml of anhydrous methylenechloride and, after stirring for one hour at ambient temperature, 6.3 gof 2-benzoyl-4-chlorobenzenesulphonyl chloride are added dropwise. Afterstirring for 12 hours, the reaction medium is evaporated to drynessunder vacuum, taken up with water and extracted with ethyl acetate. Theorganic phase which is washed with water until the washings are free ofCl⁻ ions is dried over sodium sulphate and evaporated to dryness undervacuum.

By purification on a silica column, eluting with a 5:1 mixture ofhexane:ethyl acetate, the pure product is obtained in the form ofcrystals.

C₂₆ H₃₄ ClNO₅ S (508.08); yield: 80%; m.p. 33°-34° C.

The compounds IC-1741 and 1742 are prepared in a similar way.

Example 19 Preparation of11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanamide a)Preparation of11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoyl chloride.

19 g of redistilled thionyl chloride are added to 10.3 g of11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acid in130 ml of anhydrous benzene. After refluxing for 2 hours, the reactionmedium is evaporated to dryness under vacuum and it gives a colourlessoil which is used without further purification.

C₂₄ H₂₈ Cl₃ NO₄ S (532.91); yield: 98%

b) Preparation of11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanamide

A solution of 2 g of11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acidchloride in 15 ml of anhydrous benzene is saturated with ammonia at 10°C. After stirring for two hours, the reaction medium is evaporated todryness under vacuum, the residue is taken up with water and thenextracted with ethyl acetate. After evaporation, the organic phase givescrystals which are recrystallized in benzene (1.22 g).

C₂₄ H₃₀ Cl₂ N₂ O₄ S (513.48); yield: 70% m.p. 95°-97° C.

The compounds in Table I below were prepared according to the processdescribed in Example 6.

                                      TABLE I                                     __________________________________________________________________________     ##STR116##                                                                   Number                                                                        of                      Empirical Molecular                                                                           Melting                               compounds                                                                            R.sub.1                                                                          R.sub.2                                                                         R.sub.3 n   formula   mass  point                                                                              Yield                            __________________________________________________________________________    1564   NO.sub.2                                                                         H COOH    1   C.sub.15 H.sub.12 N.sub.2 O.sub.7 S                                                     364.34                                                                              120°                                                                        67%                              1565   Cl H COOH    1   C.sub.15 H.sub.12 ClNO.sub.5 S                                                          353.78                                                                              125°                                                                        59%                              1566   NO.sub.2                                                                         H COOH    3   C.sub.17 H.sub.16 N.sub.2 O.sub.7 S                                                     393.39                                                                              162°                                                                        66%                              1567   Cl H COOH    3   C.sub.17 H.sub.16 ClNO.sub.5 S                                                          381.84                                                                              148°                                                                        60%                              1568   NO.sub.2                                                                         H COOH    5   C.sub.19 H.sub.20 N.sub.2 O.sub.7 S                                                     420.45                                                                              100°                                                                        65%                              1569   Cl H COOH    5   C.sub.19 H.sub.20 ClNO.sub.5 S                                                          409.90                                                                               94°                                                                        78%                              1570   Cl Cl                                                                              COOH    5   C.sub.19 H.sub.19 Cl.sub.2 NO.sub.5 S                                                   444.35                                                                              128°                                                                        40%                              1571   NO.sub.2                                                                         H COOH    10  C.sub.24 H.sub.30 N.sub.2 O.sub.7 S                                                     490.58                                                                               67°                                                                        87%                              1572   Cl H COOH    10  C.sub.24 H.sub.30 ClNO.sub.5 S                                                          480.03                                                                               70°                                                                        77%                              1573   Cl Cl                                                                              COOH    3   C.sub.17 H.sub.15 Cl.sub.2 NO.sub.5 S                                                   416.279                                                                             112°                                                                        27%                              1574   Cl Cl                                                                              COOH    10  C.sub.24 H.sub.29 Cl.sub.2 NO.sub.5 S                                                   514.47                                                                               99°                                                                        77%                              1575   Cl Cl                                                                              COOH    1   C.sub.15 H.sub.11 Cl.sub.2 NO.sub.5 S                                                   388.22                                                                              166°                                                                        55%                              1682   H  H COOH    10  C.sub.24 H.sub.37 NO.sub.5 S                                                            445.58                                                                               70°                                                                        65%                              1683   H  H COOH    11  C.sub.25 H.sub.33 NO.sub.5 S                                                            459.61                                                                               80°                                                                        65%                              1740   Cl H COOC.sub.2 H.sub.5                                                                    10  C.sub.26 H.sub.34 ClO.sub.5 S                                                           508.08                                                                              33-34                                                                              80%                              1741   Cl H COOC.sub.2 H.sub.5                                                                    5   C.sub.21 H.sub.24 ClO.sub.5 S                                                           437.94                                                                              55   55%                              1742   Cl H COOC.sub.2 H.sub.5                                                                    7   C.sub.23 H.sub.28 ClO.sub.5 S                                                           465.99                                                                               45  70%                              1743   Cl Cl                                                                              COOH    7   C.sub.21 H.sub.23 Cl.sub.2 O.sub.5 S                                                    472.38                                                                              76   60%                              1744   Cl H COOH    7   C.sub.21 H.sub.24 ClN.sub.5 S                                                           437.94                                                                              96   60%                              1745   Cl H CN      5   C.sub.19 H.sub.19 ClNO.sub.3 S                                                          390.89                                                                              syrupy                                                                             95%                              1755   Cl Cl                                                                              COOH    11  C.sub.25 H.sub.31 Cl.sub.2 NO.sub.5 S                                                   528.50                                                                              76-78                                                                              58%                              1760   Cl Cl                                                                              CONH.sub.2                                                                            10  C.sub.24 H.sub.30 Cl.sub.2 N.sub.2 O.sub.4                                              513.48                                                                              95-97                                                                              65%                              __________________________________________________________________________

Using the startng products (sulphochlorides and amino acids describedabove in the preparation of the compounds of the invention), thefollowing products are obtained:

12-[4-chloro-2(4-chlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[4-chloro-2-(4-chlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-[4-chloro-2-(4-chlorobenzoyl)benzenesulphonamido]octanoic acid,

6-8 4-chloro-2-(4-chlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-[4-chloro-2-(2,4-dichlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[4-chloro-2-(2,4-dichlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-]4-chloro-2-(2,4-dichlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[4-chloro-2-(2,4-dichlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-[2-(4-chlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[2(4-chlorobenzoyl)benzenesulphonamido]undecanoic acid,

8[2-(4-chlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[2-(4-chlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-[2-(2,4-dichlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[2-(2,4-dichlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-2-(2,4-dichlorobenzoyl)benzenesulphonamido]octanoic acid,

6-2-(2,4-dichlorobenzoyl)benzenesulphonamido]hexanoic acid.

The compounds in Table II below were prepared according to the processdescribed in Example 6.

                                      TABLE II                                    __________________________________________________________________________     ##STR117##                                                                   Number                                                                        of                         Molecular                                                                           Melting                                      Compounds                                                                           R.sub.1                                                                          R.sub.2                                                                          R.sub.3                                                                          n  Empirical formula                                                                      mass  point                                                                              Yield                                   __________________________________________________________________________    1684  H  H  H  10 C.sub.24 H.sub.31 NO.sub.5 S                                                           445.58                                                                              80°                                                                         65%                                     1685  H  H  H  11 C.sub.25 H.sub.33 NO.sub.5 S                                                           459.61                                                                              70°-75°                                                              65%                                     1736  Cl H  H  11 C.sub.25 H.sub.32 CINO.sub.5 S                                                         494.05                                                                              75°                                                                         41%                                     1737  Cl H  H  10 C.sub.24 H.sub.30 CINO.sub.5 S                                                         480.03                                                                              79°-80°                                                              43%                                     1761  Cl Cl H  10 C.sub.24 H.sub.29 Cl.sub.2 NO.sub.5 S                                                  514.47                                                                              80°                                                                         60%                                     1762  Cl Cl H  11 C.sub.25 H.sub.31 Cl.sub.2 NO.sub.5 S                                                  528.49                                                                              93°                                                                         67%                                     1763  Cl Cl Cl 10 C.sub.24 H.sub.28 Cl.sub.3 NO.sub.5 S                                                  548.91                                                                              94°                                                                         38%                                     1764  Cl Cl Cl 11 C.sub.25 H.sub.30 Cl.sub.3 NO.sub.5 S                                                  562.94                                                                              88°                                                                         62%                                     __________________________________________________________________________

Using the starting products (sulphochlorides and amino acids describedabove in the preparation of the compounds of the invention), thefollowing products are obtained:

12-(3-benzoyl-4-chlorobenzenesulphonamido)dodecanoic acid,

11-(3-benzoyl-4-chlorobenzenesulphonamido)undecanoic acid,

8-3-benzoyl-4-chlorobenzenesulphonamido)octanoic acid,

6(3-benzoyl-4-chlorobenzenesulphonamido)hexanoic acid,

12-[3-(2,4-dichlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[3-(2,4-dichlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-[3-(2,4-dichlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[3-(2,4-dichlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-[3-(4-chlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11-[3-(4-chlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-[3-(4-chlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[3-(4-chlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-(4-chloro-3-(2,4-dichlorobenzoyl)benzenesulphonamico]-undecanoicacid,

11-[4-chloro-3-(2,4-dichlorobenzoyl)benzenesulphonamido]-undecanoicacid,

8-[4-chloro-3-(2,4-dichlorobenzoyl)benzenesulphonamido]-octanoic acid,

6-[4-chloro-3-(2,4-dichlorobenzoyl)benzenesulphonamido]-hexanoic acid.

The compounds in Table III below were prepared according to the processdescribed in Example 6.

                                      TABLE III                                   __________________________________________________________________________     ##STR118##                                                                   Number                Molecular                                                                            Melting                                          of    R.sub.1                                                                          n  Empirical formula                                                                       mass   point                                                                              Yield                                       __________________________________________________________________________    1686  H  10 C.sub.24 H.sub.31 NO.sub.5 S                                                            445.58 128°                                                                        65%                                         1687  H  11 C.sub.25 H.sub.33 NO.sub.5 S                                                            459.61 172°                                                                        75%                                         1739  Cl 11 C.sub.25 H.sub.32 CINO.sub.5 S                                                          494.10 107°                                                                        50%                                         __________________________________________________________________________

Using the starting products (sulphochlorides and amino acids describedin the preparation of the compounds of the invention), the followingproducts are obtained:

12-(4-benzoyl-3-chlorophenylbenzenesulphonamido)dodecanoic acid,

11-(4-benzoyl-3-chlorophenylbenzenesulphonamido)undecanoic acid,

8-(4-benzoyl-3-chlorophenylbenzenesulphonamido)octanoic acid,

6-(4-benzoyl-3-chlorophenylbenzenesulphonamido)hexanoic acid,

12[-4-(8-chlorobenzoyl)benzenesulphonamido]dodecanoic acid,

11[-4-(4-chlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-[4-(4-chlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[4-(4-chlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-[4-(2,4-dichlorobenzoyl)benzenesulphonamido]doecanoic acid,

11-[4-(2,4-dichlorobenzoyl)benzenesulphonamido]undecanoic acid,

8-[4-(2,4-dichlorobenzoyl)benzenesulphonamido]octanoic acid,

6-[4-(2,4-dichlorobenzoyl)benzenesulphonamido]hexanoic acid,

12-4-chloro-4-(2,4-dichlorobenzoyl)benzenesulphonamido]-dodecanoic acid,

11-[4-chloro-4-(2,4-dichlorobenzoyl)benzenesulphonamido]-undecanoicacid,

8-[4-chloro-4-(2,4-dichorobenzoyl)benzenesulphonamido]-odanoic acid,

6-[4-chloro-4-(2,4-dichlorobenzoyl)benzenesulphonamido]-hexanoic acid,

The compounds in Table IV below were prepared according to the processdescribed in Example 7.

                                      TABLE IV                                    __________________________________________________________________________     ##STR119##                                                                   Number                                                                        of           Empirical Molecular                                                                           Melting                                                                             Yield                                      compounds                                                                           R.sub.1                                                                          R.sub.2                                                                         n formula   mass  point °C.                                                                    %                                          __________________________________________________________________________    1688  Cl H 10                                                                              C.sub.35 H.sub.51 CIN.sub.2 O.sub.9 S                                                   743.38                                                                              100-110                                                                             60                                         1689  Cl H 11                                                                              C.sub.37 H.sub.55 CIN.sub.2 O.sub.9 S                                                   769.42                                                                              125   50                                         __________________________________________________________________________

Using the starting products (sulphochlorides and amino acids describedabove in the preparation of the compounds of the invention), thefollowing products are obtained:

8-{3-[3-(7-carboxyheptylsulphamoyl)benzoyl]-4-chlorobenzenesulphonamido}octanoicacid,

6-{3-[3-(5-carboxypentylsulphamoyl)benzoyl]-4-chlorobenzenesulphonamido}hexanoicacid,

12-{2-[3-(11-carboxyundecylsulphamoyl)benzoyl]-3-chlorobenzenesulphonamido}dodecanoicacid,

11-{2-[3-(10-carboxydecylsulphamoyl)benzyl]-3-chlorobenzenesulphonamido}undecanoicacid,

8-{2-[3-(7-carboxyheptylsulphamoyl)benzoyl]-3-chlorobenzenesulphonamido}octanoicacid,

6-{2-[3-(5-carboxypentylsulphamoyl)benzoyl]-3-chlorobenzenesulphonamido}hexanoicacid,

12-{4-[3-(11-carboxyundecylsulphamoyl)benzoyl]-2-chlorobenzenesulphonamido}dodecanoicacid,

11-{4-[3-(10-carboxydecylsulphamoyl)benzoyl]-3-chlorobenzenesulphonamido}undecanoicacid,

8-{4-[3-(7-carboxyheptylsulphamoyl)benzoyl]-2-chlorobenzenesulphonamido}octanoicacid, and

6-{4-[3-(5-carboxypentylsulphamoyl)benzoyl]-2-chlorobenzenesulphonamido}hexanoicacid.

The compounds in Table V below were prepared according to the processdescribed in Example 8.

                                      TABLE V                                     __________________________________________________________________________     ##STR120##                                                                    compoundsNumber of                                                                  R.sub.1                                                                             R.sub.2                                                                          ##STR121##                                                                             n                                                                               Empirical formula                                                                       massMolecular                                                                       point °C.Melting                                                            Yield %                       __________________________________________________________________________    1340  H     H                                                                                 ##STR122##                                                                            3 C.sub.20 H.sub.24 N.sub.2 O.sub.4 S                                                     388.49                                                                              121  65                             1341  H     H                                                                                 ##STR123##                                                                            2                                                                                ##STR124##                                                                             410.93                                                                              166  45                             1342  H     H                                                                                 ##STR125##                                                                            3 C.sub.18 H.sub.22 N.sub.2 O.sub.3 S                                                     382.92                                                                              153  45                             1343  Cl    H                                                                                 ##STR126##                                                                            2 C.sub.19 H.sub.21 ClN.sub.2 O.sub.4 S                                                   408.91                                                                              157  70                             1344  Cl    H                                                                                 ##STR127##                                                                            3 C.sub.20 H.sub.23 ClN.sub.2 O.sub.4 S                                                   422.94                                                                              116  80                             1345  Cl    H                                                                                 ##STR128##                                                                            3 C.sub.18 H.sub.21 ClN.sub.2 O.sub.3 S CH.sub.3                                SO.sub.3 H                                                                              477.01                                                                              164  25                             1354  NO.sub.2                                                                            H                                                                                 ##STR129##                                                                            2 C.sub.19 H.sub.21 N.sub.3 O.sub.6 S                                                     419.46                                                                              138  50                             1360  Cl    H                                                                                 ##STR130##                                                                            2 C.sub.19 H.sub.23 ClN.sub.2 O.sub.3 S                                                   431.89                                                                              125  45                             1361  NO.sub.2                                                                            H                                                                                 ##STR131##                                                                            3 C.sub.20 H.sub.23 N.sub.3 O.sub.6 S                                                     433.49                                                                              129  66                             1362  NO.sub.2                                                                            H                                                                                 ##STR132##                                                                            2 C.sub.18 H.sub.21 N.sub.3 O.sub.5 S                                                     391.45                                                                              200  30                             1409  H     Cl                                                                                ##STR133##                                                                            3 C.sub.18 H.sub.21 ClN.sub.2 O.sub.3 S                                                   380.90                                                                               98  42                             1410  H     Cl                                                                                ##STR134##                                                                            3 C.sub.20 H.sub.23 ClN.sub.2 O.sub.4 S                                                   422.94                                                                              130  55                             __________________________________________________________________________

The compounds in Tables VI and VIa below were prepared according toExample 9.

                  TABLE VI                                                        ______________________________________                                         ##STR135##                                                                   Number of     Empirical  Molecular                                                                             Melting Yield                                compounds                                                                             n     formula    mass    point in °C.                                                                   %                                    ______________________________________                                        1738    3     C.sub.15 H.sub.15 NO.sub.5 S.sub.2                                                       353.42  128-130 60                                   ______________________________________                                    

                  TABLE VIa                                                       ______________________________________                                         ##STR136##                                                                   Number                                                                        of com-            Empirical Molec- Melting                                                                              Yield                              pounds R.sub.1                                                                             n     formula   ular mass                                                                            point °C.                                                                     %                                  ______________________________________                                        1813   Cl    11    C.sub.23 H.sub.30 ClNO.sub.5 S.sub.2                                                    500.08 74-75  73                                 1815   Cl    10    C.sub.22 H.sub.28 ClNO.sub.5 S.sub.2                                                    486.05 62-63  66                                 ______________________________________                                    

The compounds in Table VII below are prepared according to Example 15.

                                      TABLE VII                                   __________________________________________________________________________     ##STR137##                                                                   Number of      Chained       Molecular                                                                           Melting                                                                            Yield                                 compounds                                                                           R.sub.1                                                                          R.sub.2                                                                         R.sub.3                                                                         n position                                                                           Empirical formula                                                                      mass  point °C.                                                                   %                                     __________________________________________________________________________    1796  5-Cl                                                                             Cl                                                                              H 10                                                                              2-   C.sub.24 H.sub.31 Cl.sub.2 NO.sub.5 S                                                  516.48                                                                              125-130                                                                            66                                    1807  2-Cl                                                                             Cl                                                                              Cl                                                                              11                                                                              5-   C.sub.25 H.sub.32 Cl.sub.3 NO.sub.5 S                                                  564.96                                                                              113.4                                                                              85                                    1810  2-Cl                                                                             H H 11                                                                              5-   C.sub.25 H.sub.34 ClNO.sub.5 S                                                         496.02                                                                              122  83                                    __________________________________________________________________________

The compounds in Table VIIa below were prepared according to Example 9and Example 15.

                  TABLE VIIa                                                      ______________________________________                                         ##STR138##                                                                   Number                                                                        of com-            Empirical Molec- Melting                                                                              Yield                              pounds R.sub.1                                                                             n     formula   ular mass                                                                            point °C.                                                                     %                                  ______________________________________                                        1816   Cl    10    C.sub.22 H.sub.30 ClNO.sub.5 S.sub.2                                                    488.07 109    50                                 1817   Cl    11    C.sub.23 H.sub.32 ClNO.sub.5 S.sub.2                                                    502.10 117-118                                                                              59                                 ______________________________________                                    

The compounds in Table VIII below were prepared according to Example 16.

                                      TABLE VIII                                  __________________________________________________________________________     ##STR139##                                                                   Number of    Chain         Molecular                                                                           Melting                                                                            Yield                                   compounds                                                                           R.sub.1                                                                          R.sub.2                                                                         n postion                                                                            Empirical formula                                                                      mass  point °C.                                                                   %                                       __________________________________________________________________________    1797  5-Cl                                                                             Cl                                                                              10                                                                              2-   C.sub.24 H.sub.31 Cl.sub.2 NO.sub.4 S                                                  500.49                                                                              77-80                                                                              49                                      1808  2-Cl                                                                             H 10                                                                              5-   C.sub.24 H.sub.32 ClNO.sub.4 A                                                         467.04                                                                              88-90                                                                              30                                      __________________________________________________________________________

The new compounds of the invention and their physiologically acceptableorganic or inorganic salts have remarkable pharmacological properties.

Among the physiologically acceptable salts of the compounds of theinvention, the following may be mentioned in particular:

as regards salts formed from an acid: alkali metal or alkaline earthmetal salts or salts of an organic base, such as meglumate andaceglumate;

as regards salts formed from amines: hydrochlorides, sulphates,phosphates, methanesulphonates, tartrates, acetates, fumarates,succinates, pyruvates, phenoxyacetates, lactates, citrates and maleates.

The salts of the medicinal products according to the invention are:

1. Either those formed from a salification of the carboxyl group -COOHin compounds of the following formula: ##STR140##

2. Or the salts formed from a salification with a strong base (NaOH orKOH) of the --NH and --COOH groups in compounds of the followingformula: ##STR141##

3. Or the salts of the compounds obtained by the salification of thesubstituent amino group of the aromatic ring in compounds of thefollowing formula: ##STR142##

4. Or the salts of the compounds obtained by the salification of Y, whenY represents NH₂, NHR₆ or NR₆ R₇.

In the first case, the unsalified compound is converted into the salt byreacting together, in a manner known per se, the base and product of theinvention, in equimolecular quantities.

In the second case, the unsalified compound is converted into the saltby reacting together, in a manner known per se, two moles of the baseand one mole of the product of the invention, in equimolecularquantities.

In the third case and the fourth case, the unsalified compound isconverted into the salt by reacting together, in a manner known per se,the acid and the product of the invention, in equimolecular quantities.

The compounds according to the invention exert an anti-inflammatory andanalgesic effect. Some of them strongly and selectively block thebiosynthesis of the leukoytrienes B₄ (at the level of thepolymorphonuclear leukocytes) involved in inflammatory processes, andthe leukotrienes C₄ involved in allergic reactions such as asthma andcertain types of allergic diseases.

The compounds according to the invention are also distinguished by thefact that they are devoid of toxicity at the active doses.

Their therapeutic index is compatible with their use as a medicinalproduct.

By way of example, various experiments for demonstrating thepharmacological properties and the good tolerability of the compoundsaccording to the invention are reported below.

I - Anti-inflammatory activity 1) Kaolin-induced arthritis test

1.1 First experiment:

The invention of 0.05 ml of a sterile 10% strength suspension of kaolininto the metatarsal flexor sheath of the hind foot of a rat initiallyinduces an oedematous reaction. An inflammatory arthritis then forms.

The early oedematous reaction appears from the first hour, and reachesits maximum between the fourth hour and the sixth hour. This is themanifestation of interest. The assessment of the volume of the footenables the action of substances on the oedematous reaction to bestudied. The measurements are carried out using a Giono and Chevilardplethysmometer.

The test products are administered orally (stomach tube) one hour beforethe injection of the kaolin.

The results are expressed as a percentage decrease in the inflammationin the treated animals compared with a control series of animals.

The batches are of 10 animals per dose and 10 control animals.

The results are also compared with series of animals treated with areference product, ketoprofen.

The results relating to the compounds of the invention are collated inTable IX below.

The figures shown represent the mean of 10 animals.

                  TABLE IX                                                        ______________________________________                                                25 mg/kg   50 mg/kg 100 mg/kg                                         ______________________________________                                        Ketoprofen                                                                              -30%         -51%     -73%                                          1573      -15%         -30%     -52%                                          1570      -10%         -25%     -52%                                          1572      -17%         -26%     -50%                                          1565      -15%         -20%     -45%                                          1568      -15%         -18%     -40%                                          1575      -18%         -21%     -37%                                          1569      -28%         -30%     -45%                                          1567      -12%         -15%     -20%                                          1410      -18%         -32%     -57%                                          1361      -25%         -30%     -48%                                          1340      -10%         -25%     -45%                                          1344      -10%         -15%     -18%                                          1343      --           --       --                                            1571      -17%         -26%     -50%                                          1682      -35%         -35%     -40%                                          1683      -25%         -30%     -40%                                          1684      -28%         -42%     -45%                                          1686      -50%         -50%     -50%                                          1687      -23%         -28%     -50%                                          1688      -25%         -28%     -48%                                          ______________________________________                                    

The results show that, at a dose of 100 mg/kg, the majority of thecompounds tested show a very distinct anti-inflammatory activity whileshowing the advantage, compared with ketoprofen, of not giving rise toadverse side effects, as a consequence of the absence of an effect onthe biosynthesis of prostaglandins.

1.2 Second experiment:

In a second experiment, a more elaborate study was performed in order toascertain the effect of the products, on the one hand on the acute phaseof the inflammatory reaction (measured by the volume of the foot at the8th hour), and on the other hand on the chronic phase (activity measuredby the weight of the foot at the 12th hour).

As in the previous experiment, ketoprofen was used as the comparativeproduct:

Results for the Acute Phase

The results are expressed as a percentage significant decrease in thevolume of the treated foot compared with the controls. They are recordedin Table IXa below:

                  TABLE IXA                                                       ______________________________________                                                                 50%                                                         DOSE TESTED       ACTIVE                                               PRODUCT  25 mg/kg 50 mg/kg 100 mg/kg                                                                              DOSE                                      ______________________________________                                        1574     -60 ± 6                                                                             -65 ± 6                                                                             -68 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -60 ± 5                                                                             -68 ± 5                                                                             -68 ± 5                                         1736     -45 ± 5                                                                             -50 ± 5                                                                             -55 ± 5                                                                            50 mg/kg                                   Ketoprofen                                                                             -47 ± 6                                                                             -48 ± 5                                                                             -55 ± 5                                         1755     -48 ± 5                                                                             -50 ± 5                                                                             -55 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -45 ± 6                                                                             -48 ± 2                                                                             -50 ± 5                                         1761     -38 ± 5                                                                             -45 ± 5                                                                             -50 ± 5                                                                            100 mg/kg                                  Ketoprofen                                                                             -40 ± 5                                                                             -48 ± 5                                                                             -60 ± 5                                         1763     -35 ± 5                                                                             -45 ± 5                                                                             -50 ± 5                                                                            100 mg/kg                                  Ketoprofen                                                                             -37 ± 5                                                                             -48 ± 6                                                                             -52 ± 3                                         1764     -45 ± 5                                                                             -55 ± 5                                                                             -60 ± 5                                                                            50 mg/kg                                   Ketoprofen                                                                             -47 ± 6                                                                             -53 ± 3                                                                             -58 ± 4                                         1796     -50 ± 5                                                                             -55 ± 5                                                                             -60 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -48 ± 5                                                                             -55 ± 5                                                                             -58 ± 5                                         1797     -50 ± 5                                                                             -55 ± 5                                                                             -60 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -30 ± 5                                                                             -55 ± 5                                                                             -58 ± 5                                         ______________________________________                                    

Results for the Chronic Phase

The results are expressed as a percentage significant decrease in theweight of the treated foot compared with the controls, and are recordedin TABLE IXb below:

                  TABLE IXb                                                       ______________________________________                                                                 50%                                                         DOSE TESTED       ACTIVE                                               PRODUCT  25 mg/kg 50 mg/kg 100 mg/kg                                                                             DOSE                                       ______________________________________                                        1574     -58 ± 5                                                                             -60 ± 5                                                                             -60 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -58 ± 5                                                                             -65 ± 5                                                                             -65 ± 5                                         1736     -45 ± 5                                                                             -55 ± 5                                                                             -58 ± 5                                                                            50 mg/kg                                   Ketoprofen                                                                             -48 ± 5                                                                             -55 ± 5                                                                             -60 ± 5                                         1755     -45      -55      -58     25 mg/kg                                   Ketoprofen                                                                             -44 ± 5                                                                             -52 ± 6                                                                             -55 ± 5                                         1761     -40 ± 5                                                                             -45 ± 5                                                                             -50 ± 5                                                                            100 mg/kg                                  Ketoprofen                                                                             -45 ± 5                                                                             -50 ± 6                                                                             -55 ± 7                                         1763     -38 ± 5                                                                             -40 ± 5                                                                             -48 ± 5                                                                            100 mg/kg                                  Ketoprofen                                                                             -45 ± 5                                                                             -48 ± 5                                                                             -55 ±  5                                        1764     -45 ± 5                                                                             -52 ± 5                                                                             -58 ± 5                                                                            50 mg/kg                                   Ketoprofen                                                                             -47 ± 5                                                                             -51 ± 5                                                                             -57 ± 5                                         1796     -50 ± 5                                                                             -52 ± 5                                                                             -58 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -50 ± 5                                                                             -52 ± 5                                                                             -55 ± 5                                         1797     -50 ± 5                                                                             -58 ± 5                                                                             -60 ± 5                                                                            25 mg/kg                                   Ketoprofen                                                                             -50 ± 5                                                                             -55 ± 5                                                                             -56 ± 5                                         ______________________________________                                    

2) Carragheenin-Induced Oedema Test

In this test, 10 rats are used per test compound of the invention.Control batches of 10 rats also receive either the comparative compound(ketoprofen) or exclusively an NaCl solution.

An injection of carragheenin into the base of the hind foot of a ratinduces an oedema, the volume of which is measured with a Lenceplethysmometer (technique similar to that of C.A. Winter, E.A. Risleyand G.W. Nuss, Proc. Soc. Exp. Biol. Med. 1962, 111, 544 and P. Lence,Arch. Inv. Pharmacodyn. 1962, 136, 237).

The compounds of the invention are administered orally (stomach tube)one hour before the injection of carragheenin.

The carragheenin is suspended at a concentration of 1% in a 0.9%isotonic sodium chloride solution. The volume injected into the rat'sfoot is 0.20 ml.

The volume of the foot is measured before the injection and 3 hourslater. The antagonistic effect of the products towards carragheenin isreflected in the inhibition of the volume of the oedema compared withcontrol rats. The latter receive only isotonic NaCl solution underidentical conditions.

The results are expressed as a percentage inhibition of the inflammationcompared with the control rats (mean of 10 animals).

2.1 First experiment:

The results are collated in Table X below:

                  TABLE X                                                         ______________________________________                                                25 mg/kg   50 mg/kg 100 mg/kg                                         ______________________________________                                        Ketoprofen                                                                              -25%         -45%     -65%                                          1573      -17%         -28%     -50%                                          1570      -20%         -29%     -40%                                          1572      -18%         -25%     -49%                                          1565      -18%         -22%     -49%                                          1568      -15%         -20%     -35%                                          1575      -15%         -18%     -35%                                          1569      -30%         -35%     -50%                                          1567       -8%         -10%     -10%                                          1410      -15%         -25%     -48%                                          1361      -15%         -25%     -45%                                          1340       -5%          -5%     -10%                                          1344      --           --       --                                            1343       -7%          -8%      -8%                                          1571      -23%         -27%     -48%                                          1682      -33%         -42%     -45%                                          1683      -25%         -30%     -35%                                          1684      -30%         -45%     -55%                                          1686      -50%         -50%     -55%                                          1687      -25%         -30%     -48%                                          1688      -25%         -32%     -50%                                          ______________________________________                                    

2.2 Second experiment:

The results are collated in Table Xa below:

                  TABLE Xa                                                        ______________________________________                                                 DOSE                                                                 PRODUCT    25 mg/kg    50 mg/kg  100 mg/kg                                    ______________________________________                                        1574       -40% ± 5 -43% ± 5                                                                             -45% ± 5                                  Ketoprofen -45% ± 5 -50% ± 5                                                                             -50% ± 5                                  1736       -45% ± 5 -48% ± 5                                                                             -55% ± 5                                  Ketoprofen -48% ± 6 -50% ± 3                                                                             -60% ± 5                                  1755       -45% ± 5 -52% ± 5                                                                             -55% ± 5                                  Ketoprofen -44% ± 5 -55% ± 6                                                                             -58% ± 6                                  1761       -30% ± 5 -35% ± 5                                                                             -45% ± 5                                  Ketoprofen -35% ± 2 -40% ± 5                                                                             -55% ± 5                                  1763       -30% ± 5 -35% ± 5                                                                             -45% ± 5                                  Ketoprofen -35% ± 5 -45% ± 6                                                                             -55% ± 3                                  1764       -45% ± 5 -48% ± 5                                                                             -52% ± 5                                  Ketoprofen - 47% ± 5                                                                              -49% ± 7                                                                             -50% ± 5                                  1796       -45%        -48%      -55%                                         Ketoprofen -50% ± 5 -50% ± 5                                                                             -55% ± 5                                  1797       -45% ± 5 -48% ± 5                                                                             -55% ± 5                                  Ketoprofen -45% ± 5 -50% ± 5                                                                             -55% ± 5                                  ______________________________________                                    

3) Test of experimental granuloma induced by foreign body.

3.1 First experiment

Study of the following compounds:

1573, 1570, 1572, 1341, 1361, 1410.

This test consists in studying the subacute cellular phase which isdeveloped in the 8 days which follow the implantation of a foreign body,a sponge of non-resorbable plastic, in the dorsal subcutaneousconnective tissue in rats.

The granulomas formed are removed 8 days after the implantation; ahistological study is carried out after fixing the tissue and stainingsections with hematein/ eosin. The observation is more especiallyconcerned with the cell population of the primary phase of the formationof the granulation tissue: the reticulohistocytic cells, lymphocytes andmore especially the macrophages.

The animals used are Wistar rats weighing 120-140 g and of the sameorigin, maintained under the same conditions of housing throughout thetreatment (8 days).

The compounds of the invention are administered orally, in a gumsuspension, in the morning in a fasted state, using an oesophageal tube.

After 8 days of treatment, the rats are sacrificed by decapitation andthe granulomas removed and prepared for the purpose of histologicalexamination.

The experiment conditions are as follows:

The animals are distributed in batches of 10;

Each test product is administered at 2 doses, of 50 and 100 mg,respectively, to 2 batches of 10 animals;

Ketoprofen is used by way of reference product at the same 2 doses andunder the same conditions; and

A batch of 10 control animals receives no treatment.

The results are shown in Table XI below.

                  TABLE XI                                                        ______________________________________                                        Compound                                                                      No.                                                                           ______________________________________                                        1573     At both doses, the activity is very distinct, the                             connective tissue is of low density and does not                              show the characteristics of an inflammatory tissue.                  1570     The anti-inflammatory activity is exhibited at the                            dose of 50 mg/kg and is distinct for the dose of                              100 mg/kg.                                                           1572     The anti-inflammatory activity is exhibited at the                            dose of 50 mg/kg and is distinct for the dose of                              100 mg/kg.                                                           1361     The anti-inflammatory activity is exhibited at both                           doses without, however, inhibiting the formation of                           a connective tissue of the scar type.                                1410     The inflammatory reaction is attenuated at both                               doses. The action manifests itself, in particular,                            by the absence of a congestive reaction of the                                granulation tissue.                                                  1341     Inflammatory reaction distinctly attenuated at                                both doses. The results are superior to those of                              the compound 1410.                                                   KETO-    At both doses, a very substantial decrease in the                    PROFEN   inflammatory reaction is observed.                                   CONTROL  Appearance very characteristic of a granuloma of                              the inflammatory type in the course of formation.                    ______________________________________                                    

In conclusion, all the products tested exhibited an anti-inflammatoryactivity which was reflected in a histological modification of thetissues compared with the untreated control animals.

3.2 Second experiment:

Studies of the following compounds:

1574 - 1736 - 1755 - 1761 - 1763 - 1764 - 1796 - 1797

In this experiment, on the one hand a histological study of thegranulomas is performed by sampling on day 8 (results recorded in TableXIa), and on the other hand a study of the weight of the granulomas wasperformed 10 days after the implantation (results recorded in TableXIb).

                  TABLE XIa                                                       ______________________________________                                        Compound                                                                      number                                                                        ______________________________________                                        1574    At the three doses, very distinct rarefaction of                              the inflammatory connective tissue. Connective                                tissue slack, few fibroblasts. Between the fibres,                            presence of mobile cells of the connective tissue.                            Giant cells containing a foreign body very rare.                      1736    Very distinct slowing in the formation of the                                 granulation tissue. Thin peripheral shell. Rare-                              faction of the fibroblasts. Collagen fibres thin                              and scattered. Presence of lymphocytes and poly-                              morphonuclear cells; few macrophages.                                 1755    Granuloma poorly developed. Thin collagen fibres,                             few fibroblasts. Normal vascularization. Pres-                                ence of mobile cells of the connective tissue.                                Connective tissue of low density.                                     1761    Diminished production of inflammatory granulation                             tissue compared with the control. Peripheral                                  shell of the granuloma composed of fibroblasts                                and thin collagen fibres. Presence of lymphocytes,                            macrophages and histiocytes. Under the peripheral                             shell, granulation tissue of low density, composed                            of scattered fibroblasts between which the pres-                              ence of mobile cells of the connective tissue is                              observed. Tissue well vascularized.                                   1763    Peripheral shell of low density, composed of                                  fibroblasts and of collagen fibres of low density                             scattered between the fibroblasts and the fibres.                             Presence of mobile cells of the connective tissue:                            polymorphonuclear cells, lymphocytes and histio-                              cytes, rare giant cells containing a foreign body,                            attached to the sponge fragments.                                     1764    Peripheral shell of low density and low cell                                  content. Presence of mobile cells of the connec-                              tive tissue between the fibroblasts and the col-                              lagen fibres. Presence of lymphocytes, macro-                                 phages, histiocytes and rare giant cells contain-                             ing a foreign body. Granulation tissue only                                   lightly inflammatory.                                                 1796    Presence of many mobile cells of the connective                               tissue between the fibroblasts and the (thin)                                 collagen fibres. Presence of lymphocytes, macro-                              phages and histiocytes. Peripheral shell of low                               density and low cell content. Rare giant cells                                containing a foreign body. Granulation tissue                                 only slightly inflammatory.                                           1797    Granuloma poorly developed around the foreign                                 body. Thin peripheral shell. Thin collagen                                    fibres. Normal vascularization. Presence of                                   mobile cells of the connective tissue. Under                                  the peripheral shell, connective tissue only                                  slightly inflammatory.                                                ______________________________________                                    

                  TABLE XIb                                                       ______________________________________                                                 DOSE                                                                 PRODUCT    25 mg/kg    50 mg/kg  100 mg/kg                                    ______________________________________                                        1574       -48%        -50%      -55%                                         Ketoprofen -50% ± 5 -55% ± 5                                                                             -55% ± 5                                  1736       -48% ± 5 -52% ± 5                                                                             -55% ± 5                                  Ketoprofen -46% ± 5 -50% ± 5                                                                             -55% ± 5                                  1755       -45% ± 5 -50% ± 5                                                                             -55% ± 5                                  Ketoprofen -44% ± 5 -50% ± 5                                                                             -60% ± 5                                  1761       -25% ± 5 -30% ± 5                                                                             -45% ± 5                                  Ketoprofen -30% ± 5 -40% ± 6                                                                             -55% ± 7                                  1763       -15% ± 5 -20% ± 5                                                                             -45% ± 5                                  Ketoprofen -25% ± 5 -25% ± 5                                                                             -48% ± 6                                  1764       -45% ± 5 -50% ± 5                                                                             -55% ± 5                                  Ketoprofen -48% ± 5 -50% ± -57% ± 5                                  1796       -50%        -55%      -60%                                         Ketoprofen -50% ± 5 -50% ± 5                                                                             -58% ± 6                                  1797       -50% + 5    -55% ± 5                                                                             -60% ± 5                                  Ketoprofen -50% ± 5 -50% ± 5                                                                             -55% ± 5                                  ______________________________________                                    

II - Analgesic Activity Randall and Sellitto's Test (Arch. Int.Pharmacodyn. 1957, CXI, 409-419).

Inflammation increases the sensitivity to pain, in particular topressure, and analgesics raise the threshold of the sensitivity.

The inflammation is obtained by injecting 0.1 ml of a 20% strengthaqueous suspension of brewer's yeast under the plantar aponeurosis ofone of the hind feet. The pain is induced by a force applied to theplantar surface and gradually increased by 16 g/second. The painthreshold is assessed in terms of the force necessary and sufficient toinitiate a characteristic reaction of withdrawing the foot.

The sensitivity to pain of the inflamed foot reaches a plateau 4 hoursafter the injection of the brewer's yeast, and then remains stable untilthe 6th hour. The pain threshold of the inflamed foot in control ratsweighing 140 g is reached for pressures of 50 to 60 g, whereas it isaround 160 g for the intact foot.

The action of the substance administered orally to series of 10 rats isexpressed in terms of the percentage increase in the mean painthreshold, compared with that measured in the rats of a control seriesof 10 animals which have not received a compound of the invention.

The test products are administered orally (stomach tube) one hour beforethe injection of brewer's yeast.

The comparative compound used is ketoprofen.

1. First experiment

The results are collated in Table XII below:

                  TABLE XII                                                       ______________________________________                                                25 mg/kg   50 mg/kg 100 mg/kg                                         ______________________________________                                        Ketoprofen                                                                              +22%         +55%     +78%                                          1573      +20%         +35%     +60%                                          1570      +15%         +25%     +53%                                          1572      +18%         +30%     +55%                                          1565      +18%         +28%     +42%                                          1568      +18%         +25%     +48%                                          1575      +15%         +19%     +35%                                          1569      +10%         +15%     +25%                                          1567      +12%         +15%     +20%                                          1410      +19%         +37%     +58%                                          1361      +20%         +25%     +45%                                          1340      +10%         +20%     +49%                                          1344      +18%         +18%     +25%                                          1343      +10%         +12%     +12%                                          1571      +25%         +32%     +36%                                          1682      +12%         +15%     +20%                                          1683      +15%         +20%     +30%                                          1684      +35%         +45%     +50%                                          1686      +35%         +50%     +50%                                          1687      +25%         +35%     +50%                                          1688      +25%         +32%     +50%                                          ______________________________________                                    

2. Second experiment

The results are collated in Table XIIa below:

    ______________________________________                                               DOSE                50% active                                         PRODUCT  25 mg/kg  50 mg/kg  100 mg/kg                                                                             dose                                     ______________________________________                                        1574     +45% ± 6                                                                             +50% ± 5                                                                             +50% ± 5                                                                           50 mg/kg                                 Ketoprofen                                                                             +50% ± 5                                                                             +55% ± 5                                                                             +58% ± 5                                      1736     +52%      +58%      +60%    25 mg/kg                                 Ketoprofen                                                                             +51% ± 6                                                                             +55% ± 5                                                                             +60% ± 5                                      1755     +40% ± 5                                                                             +50% ± 5                                                                             +55% ± 5                                      Ketoprofen                                                                             +38% ± 6                                                                             +52% ± 5                                                                             +55% ± 6                                      1761     +40% ± 5                                                                             +45% ± 5                                                                             +50% ± 5                                      Ketoprofen                                                                             +45% ± 2                                                                             +48% ± 5                                                                             +55% ± 5                                      1763     +40% ± 5                                                                             +42% ± 5                                                                             +45% ± 5                                      Ketoprofen                                                                             +42% ± 6                                                                             +48% ± 7                                                                             +55% ± 8                                      1764     +50% ± 5                                                                             +55% ± 5                                                                             +58% ± 5                                                                           25 mg/kg                                 Ketoprofen                                                                             +50% ± 5                                                                             +57% ± 5                                                                             +60% ± 5                                      1796     +50% ± 5                                                                             +55% ± 5                                                                             +58% ± 5                                                                           25 mg/kg                                 Ketoprofen                                                                             +49% ± 5                                                                             +50% ± 5                                                                             +55% ± 5                                      1797     +50% ± 5                                                                             +55% ± 5                                                                             +58% ± 5                                      Ketoprofen                                                                             +55% ± 5                                                                             +55% ± 5                                                                             +58% ± 5                                      ______________________________________                                    

III --Mechanism of biochemical action

Membrane phospholipids are metabolized by the action of phospholipase A₂to arachidonic acid, the latter leading via the cyclooxygenase pathwayto the biosynthesis of prostaglandins and thromboxanes, and via thelipoxygenase pathway to the biosynthesis of leukotrienes.

The products of the invention were tested, on the one hand, on the humanplatelet cyclooxygenase pathway using aggregating agents (thrombin or asub-aggregating concentration of arachidonic acid). No modification (noanticyclooxygenase effect) is detected with the products of theinvention.

Additional studies were carried out to investigate a possible activityof the products on thromboxane synthetase and on prostacyclinsynthetase, a subsequent stage in the biosynthesis of prostaglandins.

In addition, the products of the invention were tested on the5-lipoxygenase pathway using human polymorphonuclear leukocytes, andthis showed that some of them were inhibitors of 5-lipoxygenase.

1) Study of the Specific Action Towards Thromboxane Synthetase:

1.1 Human platelet suspension system

The platelets are incubated with arachidonic acid (5 μg/ml) in thepresence of increasing doses of test products (10^(-6l) M to 5×10⁻⁵ M).Platelets stimulated by arachidonic acid (AA) manufacture a large amountof thromboxane A₂ (TXA₂), which can be measured radioimmunologically inthe form of a stable metabolite TXB₂.

The assay of the amount of TXB₂ in the medium is performed after a 1- to15- minute incubation at 37° C., the measurements being made incomparison with a control suspension which has not been incubated withthe test products.

Results: These are expressed as IC₅₀, that is to say as theconcentration of the test product which permits 50% inhibition of theproduction of TXB₂.

    ______________________________________                                                        IC.sub.50                                                            Test Product                                                                           μM                                                         ______________________________________                                               1572     12                                                                   1574     8                                                                    1736     6.2                                                                  1796     7.8                                                                  1797     5                                                                    1813     11                                                            ______________________________________                                    

The IC₅₀ values obtained show that the test products are stronginhibitors of TXB₂ production.

In addition, at the doses studied (10⁻⁶ M to 5×10⁻⁵ M), it was possibleto observe a dose-response relationship for the test products withrespect to the inhibition of TXB₂ production.

1.2 Renal preparation model

Human glomeruli synthesize both thromboxanes, via thromboxanesynthetase, and prostaglandins, via prostacyclin synthetase. Theexperiment consists in stimulating glomerular cells with arachidonicacid (5 ug/ml) and in assaying radioimmunologically the amount ofthromboxane B₂ (TXB₂) and prostacyclin (PGI₂) produced in the presenceof increasing concentrations of test products (10⁻⁶ M to 5×10⁻⁵ M).

As for the previous model, the results are expressed as IC₅₀ incomparison with a control suspension.

    ______________________________________                                                        IC.sub.50                                                     Test Products     TXB.sub.2                                                                             PGI.sub.2                                           ______________________________________                                        1572              7        100                                                1574              5        100                                                1736              2.6     >50                                                 1796              3.2      50                                                 1797              4.4     >50                                                 1813              2       >50                                                 ______________________________________                                    

The IC₅₀ values obtained (<10 μM) show that the test products are stronginhibitors of TXB₂ production, whereas they are only weak inhibitors ofPGI₂ production (IC₅₀ ≧50 μM), and that it is hence possible to obtain aspecific activity towards TXB₂.

In addition, at the doses used (10⁻⁶ M to 5×10⁻⁵ M), a dose-responserelationship is observed in respect of the inhibition of TXB₂.

2) Activity in respect of the biosynthesis of leukotrienes

2.1 First experiment

Polymorphonuclear leukocytes are isolated from human blood and usedduring the 6 hours following the withdrawal. The viability of the cellsis checked by trypan blue exclusion.

5×10⁶ cells are incubated for 10 minutes at 37° C. in the presence ofthe test product dissolved in DMSO, and are stimulated with ionophore A23187 (Galbiochem, 10 μM) in PBS buffer at pH 7.4, Ca²⁺ and Mg²⁺ =1 μM.

100 ng of prostaglandin B₂ (PGB₂), dissolved in methanol, are added atthe end of the reaction to act as an internal standard.

On centrifugation, the culture supernatant is withdrawn. The latter isretrieved under argon and stored at -80° C. until analysed by HPLC.

This analysis is carried out by injecting 250 μl onto a 5 μm ODSultrasphere column (Beckmann), with a gradient of acetonitrile (20-80%)in water, at pH 7.4.

The amounts of the different products which absorb at 269 nm, i.e.leukotrienes B₄ (LTB₄), isomers of LTB₄ and oxidized metabolites ofLTB₄, are estimated by comparison with the internal standard.

The test product is used at a concentration of 40 μM.

The results recorded in the table below show the activity of thecompounds on:

1. LTB₄

2. the isomers of LTB₄

3. the oxidized metabolites of LTB₄.

They are expressed either as a percentage inhibition, or as a percentageincrease in the production of LTB₄, isomers of LTB₄ and oxidizedmetabolites of LTB₄ (designated by +).

    ______________________________________                                        Product                                                                              LTB.sub.4  Isomers    Oxidized metabolites                             ______________________________________                                        1571   60%        53%        70%                                              1572   84%        100%       90%                                              1574   95%        100%       100                                              1682   +30%       +30%       40%                                              1683   +15%       +15%       30%                                              1684   20%        35%        60%                                              1685   50%        70%        70%                                              1686    0%         5%        25%                                              1688   +35%       -35%       20%                                              1689   -30%       -30%       20%                                              1687   +16%       0          -30%                                             ______________________________________                                    

2.2 Second experiment

The experimental model is the same as that described in Section 2.1.Other products are tested by comparison with the compound of theinvention no. 1574, used as a control.

    ______________________________________                                        Results                                                                                    Percentage inhibition of                                         Test Product LTB.sub.4 formation                                              ______________________________________                                        1574          95                                                              1734          70                                                              1736         100                                                              1737          95                                                              1743          20                                                              1738          20                                                              1755         100                                                              1761         100                                                              1763         100                                                              1764         100                                                              1796         100                                                              1797         100                                                              ______________________________________                                    

The results show that, at a concentration of 40 μM, most of the testproducts very strongly inhibit a biosynthesis of LTB₄.

2.3 Third experiment

Human polymorphonuclear Leukocytes are stimulated by calcium ionophore A23187 (Calbiochem, 5 μM), in the presence or absence of the testproducts.

After 15 minutes' incubation at 37° C., assay of the leukotrienes C₄(LTC₄) is performed radioimmunologically.

The results are expressed as IC₅₀, the concentration producing 50%inhibition of the production of LTC₄, by comparison with a controlsuspension which has not been incubated in the presence of the testproducts.

    ______________________________________                                        Results                                                                                       IC.sub.50                                                            Test Product                                                                           μM                                                         ______________________________________                                               1574     3                                                                    1736     3                                                                    1796     1.7                                                                  1797     1                                                                    1813     1                                                             ______________________________________                                    

The IC₅₀ values obtained show that the products strongly inhibit theproduction of LTC₄.

A dose-response relationship is also observed between the doses tested,10⁻⁶ and 5×10⁻⁵ M, and the inhibition of the biosynthesis of LTC₄.

2.4 Fourth experiment

Human polymorphonuclear leukocytes suspended with arachidonic acid andstimulated by calcium ionophore produce leukotrienes B₄ (LTB₄).

The test consists in incubating fresh human leukocytes with arachidonicacid at a dose of 10 μg/ml to which a tracer dose of tritium-labelledarachidonic acid has been added. The leukocytes are stimulated withcalcium ionophore A 23187 (Calbiochem, 5 μM) and the amount of5-hydroxyeicosatetraenoic acid (5-HETE) and LTB₄ produced is thenassayed by HPLC.

5-HETE is the metabolite produced from arachidonic acid by5-lipoxygenase, and from which LTB₄ is produced by the action of anisomerase.

The results are expressed as an integration of the surface of the peakobtained in HPLC by comparison with that obtained with controlleukocytes which have not been incubated with the test products.

The results in brackets are expressed as a percentage inhibition of theproduction of 5-HETE and LTB₄.

    ______________________________________                                        Results                                                                       Control                                                                       leukocytes   1736     1796    1797   1813                                     ______________________________________                                        LTB4   3.419     Undetec- 152   Undetec-                                                                             Undetec-                                                table    (95.7)                                                                              table  table                                                   (100)          (100)  (100)                                  5-HETE 3.690     384      127   Undetec-                                                                             181                                                     (89.6)   (96.6)                                                                              table  (95.1)                                                                 (100)                                         ______________________________________                                    

The results show that the test products very strongly inhibit both theproduction of 5-HETE and that of LTB₄, and this shows that theinhibition takes place at the 5-lipoxygenase level.

IV--Toxicological Study

The approximate oral LD₅₀ of the following compounds was studied: 1361,1489 and 1572 in rats and mice and 1341, 1573, 1574, 1361, 1495, 1579,1489 and 1572 in mice.

The compounds were suspended in a 3% strength solution of gum arabic soas to supply, in a volume of 2 ml for the rats, the equivalent of 50,100, 200, 400 and 800 mg/kg, and, in a volume of 1 ml for the mice, 100,200, 400, 800 and 1,600 mg/kg and, for 1573 and 1579, 3,200 mg/kg.

Gavage was performed by means of a metal tube, on batches of 5 animalsfor each series.

The animals were observed daily for 14 days.

The approximate LD₅₀ values are shown in the following table.

                  TABLE XIII                                                      ______________________________________                                        Oral LD.sub.50                                                                                  Female Swiss CF mice,                                       Male Wistar rats, 200-400 g                                                                     weight 20 g                                                 Compound No.      Compound No.                                                ______________________________________                                        1361 >800 mg/kg   1341- 250 mg/kg                                             1572 >800 mg/kg   1573 >3,200 mg/kg                                           1489 >800 mg/kg   1574 >1,600 mg/kg                                                             1361 >1,600 mg/kg                                                             1572 >1,600 mg/kg                                                             1495 >1,600 mg/kg                                                             1579 >3,200 mg/kg                                                             1489 >1,600 mg/kg                                           ______________________________________                                    

The test products proved to be well tolerated orally in rats and mice.Their DL₅₀ is higher than the known one of ketoprofen.

The compounds are advantageously introduced as active principle intomedicinal products intended for the treatment of inflammatory states orof allergic states, in particular those of a cutaneous or asthmaticnature, or for the treatment of certain pathological cardiovascularconditions or renal insufficiency.

For this purpose, the compounds according to the invention are packagedwith the traditional excipients and additives, in particular those usedfor preparing tablets, powders, gelatin capsules, ampoules for oraladministration and injectable solutions.

The medicinal products of the invention can advantageously beadministered orally, in particular in the form of tablets, gelatincapsules, powders, solutions, suspensions or syrup.

The medicinal products according to the invention can also beadministered topically, such as a cream, lotion, ointment or gel.

The medicinal products according to the invention can also beadministered parenterally, for example when the active substance is insalt form.

For this reason, they are presented in the form of sterile orsterilizable solutions which are injectable or suitable for this use,for the extemporaneous preparation of injectable solutions. Thesesolutions can be presented in the form of aqueous physiologicalsolutions, especially isotonic solutions of one of these compounds, forexample isotonic glucose or saline solutions, these examples naturallynot being limiting in nature in the definition of the physiologicallyacceptable products which can be used for forming the injectableisotonic solutions.

The medicinal products according to the invention can also beadministered in the form of suppositories.

The doses to be administered will be approximately 10 to 500 mg ofactive substance per day.

In the pharmaceutical preparations intended for oral administration, theunit dose is composed of approximately 10 to approximately 500 mg, andpreferably from approximately 25 to 250 mg, of active substance per unitdose. In the pharmaceutical presentations intended for parenteraladministration, the injectable preparations contain approximately 10 to100 mg of active substance per unit dose.

We claim:
 1. A compound of the formula: ##STR143## in which: W is ═C═O,--CH₂ --or ═CHOH; Z is: ##STR144## R₁ is Cl, F, Br, NO₂, NH₂, CF₃, alkylof 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, acetamido orbenzamido;R₂ is Cl, F, Br, NO₂, NH₂, CF₃, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, acetamido or benzamido; R is H, alkyl of1 to 6 carbon atoms or benzyl; R' and R" are individually H or alkyl of1 to 4 carbon atoms; X is --(CH₂)_(r) --, --CH═CH--, ##STR145## r is 0or 1; Y is --COOR₃, ##STR146## --C.tbd.N, --NH₂, --NHR₆, --NR₆ R₇ or##STR147## R₃ is H or alkyl of 1 to 4 carbon atoms; R₄ and R₅ areindividually H or alkyl of 1 to 4 carbon atoms; R₆ and R₇ areindividually alkyl of 1 to 4 carbon atoms, or together represent analkylene group and form with the nitrogen atom a non-aromatic cyclicamine, or together represent a --(CH₂)₂ --O--(CH₂)₂ --group and formwith the nitrogen atom a morpholine group; ##STR148## is a 5- or 6-membered nonaromatic ring in which the 2 or 3 atoms which form theremainder of the ring are selected from the group consisting of C, O andN;provided that when Y is --NH₂, X is other than ##STR149## u is aninteger of 0 to 2; v is an integer of 0 to 2; p is 0 or 1; q is 0 or 1,p+q being at least 1; n is an integer of 0 to 11; m is an integer of 0to 10; t is 0 or 1; and the total number of carbon atoms in each chain

    --(CH.sub.2).sub.n --(CH).sub.t --X--CH--(CH.sub.2).sub.m -Y

is from 2 to 20;and the physiologically acceptable salts thereof.
 2. Thecompound of claim 1, wherein W is ═C═O.
 3. The compound of claim 2,wherein Z is ##STR150##
 4. The compound of claim 3, wherein Y is--COOR₃.
 5. The compound of claim 3, wherein Y is

    --NH.sub.2, --NHR.sub.6 or --NR.sub.6 R.sub.7.


6. The compound of claim 3, wherein p or q is
 0. 7. The compound ofclaim 6, wherein u+v is at least 1 and the total number of carbon atomsin each chain ##STR151## is at least
 5. 8. The compound of claim 3,wherein p is 1, q is 1, u+v is at least 1 and the total number of carbonatoms in each chain ##STR152## is at least
 5. 9. The compound of claim1, wherein W is ═CH₂.
 10. The compound of claim 1, wherein W is ═CHOH.11. The compound of claim 1, wherein p is 1 and q is
 0. 12. The compoundof claim 11, wherein Y is --COOR₃.
 13. The compound of claim 12, whereinW is ═C═O.
 14. The compound of claim 13, wherein the total number ofcarbon atoms in the chain ##STR153## is at least
 5. 15. The compound ofclaim 12, wherein W is ═CH₂.
 16. The compound of claim 5, wherein thetotal number of carbon atoms in the chain ##STR154## is at least
 5. 17.The compound of claim 12, wherein W is ═CHOH.
 18. The compound of claim17, wherein the total number of carbon atoms in the chain ##STR155## isat least
 5. 19. The compound of claim 12, wherein Z is ##STR156## andthe total number of carbon atoms in the chain ##STR157## is at least
 520. The compound of claim 11, having the formula: ##STR158##
 21. Thecompound of claim 20, wherein Y is --COOR₃.
 22. The compound of claim21, wherein W is >C═O.
 23. The Compound of claim 22, wherein the totalnumber of carbon atoms in the chain ##STR159## is at least
 5. 24. Thecompound of claim 21, wherein W is >CH₂.
 25. The compound of claim 24,wherein the total number of carbon atoms in the chain ##STR160## is atleast
 5. 26. The compound of claim 21, wherein W is >CHOH.
 27. Thecompound of claim 26, wherein the total number of carbon atoms in thechain ##STR161## is at least
 5. 28. The compound of claim 21, wherein Zis ##STR162## and the total number of carbon atoms in the chain##STR163## is at least
 5. 29. The compound of claim 20, wherein Wis >C═O and Z is ##STR164##
 30. The compound of claim 29, wherein thetotal number of carbon atoms in the chain ##STR165## is at least
 5. 31.The compound of claim 11, having the formula: ##STR166## in which R₁ andR₂ are individually Cl, F or Br and n is an integer of 3 to
 11. 32. Thecompound of claim 11, having the formula: ##STR167## in which R₁ is Cl,F or Br and n is an integer of 3 to
 11. 33. The compound of claim 11,wherein W is ═C═O and Z is ##STR168##
 34. The compound of claim 33,wherein the total number of carbon atoms in the chain. ##STR169## is atleast
 5. 35. The compound of claim 11, having the formula: ##STR170##36. A pharmaceutical composition for inhibiting the biosynthesis ofleukotrienes and for treating inflammatory, allergic or asthmaticconditions, comprising a compound of claim 1 and a pharmaceuticallyacceptable vehicle.
 37. The composition of claim 36 constituting aninjectable pharmaceutical composition; said compound of claim 1comprising 10 to 100 mg per unit dose of said composition.
 38. Thecomposition of claim 36 constituting a pharmaceutical composition fororal administration; said compound of claim 1 comprising 10 to 500 mgper unit dose of said composition.
 39. A pharmaceutical compositionforinhibiting the biosynthesis of thromboxane synthetase and fortreating a cardiovascular disorder or renal insufficiency, comprising acompound of claim 1 and a pharmaceutically acceptable vehicle.
 40. Thecomposition of claim 39 constituting an injectable pharmaceuticalcomposition; said compound of claim 1 comprising 10 to 100 mg per unitdose of said composition.
 41. The composition of claim 39 constituting apharmaceutical composition for oral administration; said compound ofclaim 1 comprising 10 to 500 mg per unit dose of said composition.
 42. Amethod for inhibiting a patient's biosynthesis of leukotrienes and/orthromboxane synthetase and for treating the patient for an inflammatory,allergic or asthmatic condition, a cardiovascular disorder or renalinsufficiency, comprising the step of: administering a compound of claim11 to the patient.